(thio)morpholine derivatives as s1p modulators

ABSTRACT

The present invention relates to (thio)morpholine derivatives of the formula (I), wherein R1 is selected from cyano, (2-4C)alkynyl, (1-4C)alkyl, (3-6C)cycloalkyl, (4-6C)cycloalkenyl, (6-8C)bicycloalkyl, (8-10C)bicyclic group, each optionally substituted with (1-4C)alkyl, phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyl optionally substituted with one or more fluoro atoms, (2-4C)alkynyl, (1-4C)alkoxy optionally substituted with one or more fluoro atoms, amino, di(1-4C)alkylamino, —SO 2 -(1-4C)alkyl, —CO-(1-4C)alkyl, —CO—O-(1-4C)alkyl, —NH—CO-(1-4C)alkyl and (3-6C)cycloalkyl, phenyl substituted with phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each optionally substituted with (1-4C)alkyl, monocyclic heterocycle optionally substituted with halogen, (1-4C)alkyl or with phenyl optionally substituted with (1-4C)alkyl, and bicyclic heterocycle optionally substituted with (1-4C)alkyl; A is selected from —CO—O—, —O—CO—, —NH—CO—, —CO—NH, —C═C—, —CCH 3 —O— and the linking group —Y—(CH 2 ) u —X— wherein Y is attached to R1 and selected from a bond, —O—, —S—, —SO—, —SO 2 —, —CH 2 —O—, —CO—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO—, —C═C— and —C≡C—; n is an integer from 1 to 10; and X is attached to the phenylene/pyridyl group and selected from a bond, —O—, —S—, —SO—, —SO 2 —, —NH, —CO—, —C═C— and —C≡C—; ring structure B optionally contains one nitrogen atom; R2 is H, (1-4C)alkyl optionally substituted with one or more fluoro atoms, (1-4C)alkoxy optionally substituted with one or more fluoro atoms, or halogen; and R3 is (1-4C)alkylene-R5 wherein the alkylene group may be substituted with (CH 2 ) 2  to form a cyclopropyl moiety or one or two halogen atoms, or R3 is (3-6C)cycloalkylene-R5 or —CO—CH 2 —R5, wherein R5 is —OH, —PO 3 H 2 , —OPO 3 H 2 , —COOH, —COO(1-4C)alkyl or tetrazol-5-yl; R4 is H or (1-4C)alkyl; R6 is one or more substituents independently selected from H, (1-4C)alkyl or oxo; W is —O—, —S—, —SO— or —SO 2 —; or a pharmaceutically acceptable salt, a solvate or hydrate thereof; with the proviso that the derivative of formula (I) is not 2-(4-ethylphenyl)-4-morpholinoethanol or 4-[4-(2-hydroxyethyl)-2-morpholinyl]benzeneacetonitrile or a pharmaceutically acceptable salt, a solvate or hydrate thereof. The compounds of the invention have affinity to S1P receptors and may be used in the treatment, alleviation or prevention of S1P receptor mediated diseases and conditions.

FIELD OF THE INVENTION

This invention relates to new (thio)morpholine derivatives havingaffinity to S1P receptors, a pharmaceutical composition containing saidcompounds, as well as the use of said compounds for the preparation of amedicament for treating, alleviating or preventing diseases andconditions in which any S1P receptor is involved or in which modulationof the endogenous S1P signaling system via any S1P receptor is involved.

BACKGROUND OF THE INVENTION

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediatesa wide variety of cellular responses, such as proliferation,cytoskeletal organization and migration, adherence- and tight junctionassembly, and morphogenesis. S1P can bind with members of theendothelial cell differentiation gene family (EDG receptors) of plasmamembrane-localized G protein-coupled receptors. To date, five members ofthis family have been identified as S1P receptors in different celltypes, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6) and S1P5(EDG-8). S1P can produce cytoskeletal re-arrangements in many cell typesto regulate immune cell trafficking, vascular homeostasis and cellcommunication in the central nervous system (CNS) and in peripheralorgan systems.

It is known that S1P is secreted by vascular endothelium and is presentin blood at concentrations of 200-900 nanomolar and is bound by albuminand other plasma proteins. This provides both a stable reservoir inextracellular fluids and efficient delivery to high-affinitycell-surface receptors. S1P binds with low nanomolar affinity to thefive receptors S1P1-5. In addition, platelets also contain S1P and maybe locally released to cause e.g. vasoconstriction. The receptorsubtypes S1P1, S1P2 and S1P3 are widely expressed and represent dominantreceptors in the cardiovascular system. Further, S1P1 is also a receptoron lymphocytes. S1P4 receptors are almost exclusively in thehaematopoietic and lymphoid system. S1P5 is primarily (though notexclusively) expressed in central nervous system. The expression of S1P5appears to be restricted to oligodendrocytes in mice, the myelinatingcells of the brain, while in rat and man expression at the level ofastrocytes and endothelial cells was found but not on oligodendrocytes.

S1P receptor modulators are compounds which signal as (ant)agonists atone or more S1P receptors. The present invention relates to modulatorsof the S1P5 receptor, in particular agonists, and preferably to agonistswith selectivity over S1P1 and/or S1P3 receptors, in view of unwantedcardiovascular and/or immunomodulatory effects. It has now been foundthat S1P5 agonists can be used in the treatment of cognitive disorders,in particular age-related cognitive decline. Although research isongoing to develop therapeutics that can be used to treat age relatedcognitive decline and dementia, this has not yet resulted in manysuccessful candidates. Therefore, there is a need for new therapeuticswith the desired properties.

DESCRIPTION OF THE INVENTION

It has now been found that (thio)morpholine derivatives of the formula(I)

-   -   wherein    -   R1 is selected from        -   cyano,        -   (2-4C)alkynyl,        -   (1-4C)alkyl,        -   (3-6C)cycloalkyl,        -   (4-6C)cycloalkenyl,        -   (6-8C)bicycloalkyl, (8-10C)bicyclic group, each optionally            substituted with (1-4C)alkyl,        -   phenyl, biphenyl, naphthyl, each optionally substituted with            one or more substituents independently selected from            halogen, (1-4C)alkyl optionally substituted with one or more            fluoro atoms, (2-4C)alkynyl, (1-4C)alkoxy optionally            substituted with one or more fluoro atoms, amino,            di(1-4C)alkylamino, —SO₂-(1-4C)alkyl, —CO-(1-4C)alkyl,            —CO—O-(1-4C)alkyl, —NH—CO-(1-4C)alkyl and (3-6C)cycloalkyl,        -   phenyl substituted with phenoxy, benzyl, benzyloxy,            phenylethyl or monocyclic heterocycle, each optionally            substituted with (1-4C)alkyl,        -   monocyclic heterocycle optionally substituted with halogen,            (1-4C)alkyl or with phenyl optionally substituted with            (1-4C)alkyl,        -   and        -   bicyclic heterocycle optionally substituted with            (1-4C)alkyl;    -   A is selected from —CO—O—, —O—CO—, —NH—CO—, —CO—NH, —C═C—,        —CCH₃—O— and the linking group —Y—(CH₂)_(n)—X— wherein        -   Y is attached to R1 and selected from a bond, —O—, —S—,            —SO—, —SO₂—, —CH₂—O—, —CO—, —O—CO—, —CO—O—, —CO—NH—,            —NH—CO—, —C═C— and —C≡C—;        -   n is an integer from 1 to 10; and

X is attached to the phenylene/pyridyl group and selected from a bond,—O—, —S—, —SO—, —SO₂—, —NH, —CO—, —C═C— and —C≡C—;

-   -   ring structure B optionally contains one nitrogen atom;    -   R2 is H, (1-4C)alkyl optionally substituted with one or more        fluoro atoms, (1-4C)alkoxy optionally substituted with one or        more fluoro atoms, or halogen; and    -   R3 is (1-4C)alkylene-R5 wherein the alkylene group may be        substituted with (CH₂)₂ to form a cyclopropyl moiety or one or        two halogen atoms, or R3 is (3-6C)cycloalkylene-R5 or        —CO—CH₂—R5, wherein R5 is —OH, —PO₃H₂, —OPO₃H₂, —COON,        —COO(1-4C)alkyl or tetrazol-5-yl;    -   R4 is H or (1-4C)alkyl;    -   R6 is one or more substituents independently selected from H,        (1-4C)alkyl or oxo;    -   W is —O—, —S—, —SO— or —SO₂—;    -   or a pharmaceutically acceptable salt, a solvate or hydrate        thereof; with the proviso that the derivative of formula (I) is        not 2-(4-ethylphenyl)-4-morpholinoethanol or        4-[4-(2-hydroxyethyl)-2-morpholinyl]benzeneacetonitrile.        display affinity for S1P receptors. In particular, compounds of        the invention show selective affinity for the S1P5 receptor over        the S1P1 and/or S1P3 receptor(s).

The use of the compound 2-(4-ethylphenyl)-4-morpholinoethanol as areagent in the production of 2-(2-arylmorpholino)ethyl esters ofnaproxen is described in Database CA [Online] Chemical AbstractsService, Columbus, OHIO, US; 2008, Hu, Ai-Xi et al, XP002558960retrieved from STN database accession no. 2008:1527686; & Huaxue Xuebao,66(22), 2553-2557 Coden: HHHPA4; ISSN: 0567-7351, 2008. Nopharmacological activity of the compound is reported.

Similarly, in Farmatsiya (Sofia), Vol. 45, no. 1, 1998, pages 3-11,XP009126794 Yordanova, K. et al. describe the use of4-[4-(2-hydroxyethyl)-2-morpholinyl]-benzeneacetonitrile as a reagent inthe production of antidepressant phenylmorpholine derivatives. Nopharmacological activity of the compound is reported.

The compounds of the invention are modulators of the S1P receptor, inparticular of the S1P5 receptor. More specifically, the compounds of theinvention are S1P5 receptor agonists. The compounds of the invention areuseful for treating, alleviating and preventing diseases and conditionsin which (any) S1P receptor(s)—in particular S1P5—is (are) involved orin which modulation of the endogenous S1P signaling system via any S1Preceptor is involved. In particular, the compounds of the presentinvention may be used to treat, alleviate or prevent CNS (centralnervous system) disorders, such as neurodegenerative disorders, inparticular—but not limited to—cognitive disorders (in particularage-related cognitive decline) and related conditions, Alzheimer'sdisease, (vascular) dementia, Nieman's Pick disease, and cognitivedeficits in schizophrenia, obsessive-compulsive behavior, majordepression, autism, multiple sclerosis, pain, etc. . . . Preferably, thecompounds of the present invention may be used to treat, alleviate orprevent cognitive disorders (in particular age-related cognitivedecline) and related conditions.

In embodiments of the invention, the ring structure B is phenylene.

In an embodiment of the invention, the compounds have the structure (II)

In another embodiment of the invention, the compounds have formula (I)wherein R3 is selected from —(CH₂)₂—OH, —CH₂—COOH, —(CH₂)₂—COOH,—(CH₂)₃—COOH, —CH₂—CHCH₃—COOH, —CH₂—C(CH₃)₂—COOH, —CHCH₃—CH₂—COOH,

—CH₂—CF₂—COOH, —CO—CH₂—COOH, 1,3-cyclobutylene-COOH, —(CH₂)₂—PO₃H₂,—(CH₂)₃—PO₃H₂, —(CH₂)₂—OPO₃H₂, —(CH₂)₃—OPO₃H₂, —CH₂-tetrazol-5-yl,—(CH₂)₂-tetrazol-5-yl and —(CH₂)₃-tetrazol-5-yl. Preferred R3 groups areselected from —CH₂—COOH, —(CH₂)₂—COOH, —(CH₂)₃—COOH, —CH₂—CHCH₃—COOH,—CH₂—C(CH₃)₂—COOH, —CHCH₃—CH₂—COOH, —(CH₂)₂—PO₃H₂, —(CH₂)₃—PO₃H₂ and—(CH₂)₂—OPO₃H₂ and in particular —(CH₂)₂—COOH and —(CH₂)₂—PO₃H₂. Mostpreferred is —(CH₂)₂—COOH.

In another embodiment, W is —O— or —S—. In preferred embodiments, W is—O—.

In a further embodiment of the invention, R4 is H or methyl and inparticular, R4 is H.

In another embodiment, the compounds have formula (I) wherein R2 is H,methyl, methoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, CI or F. In further preferred embodiments, R2 is H ortrifluoromethyl.

Further, in an embodiment of the invention, A is selected from —CO—O—,—NH—CO—, —CO—NH, —C═C—, —CCH₃—O— and the linking group —Y—(CH₂)_(n)—X—wherein Y is attached to R1 and selected from a bond, —O—, —SO₂—,—CH₂—O—, —CO—, —CO—O—, —NH—CO—, —C═C— and —C≡C—; n is an integer from 1to 7; and X is attached to the phenylene/pyridyl group and selected froma bond, —O—, —S— and —NH. Preferably, A selected from —CO—NH, —C═C—,—CCH₃—O— and the linking groups —(CH₂)_(n)—X— and —O—(CH₂)_(n)—X—. Inpreferred embodiments A is CH₂—O—.

In further embodiments of the invention, R1 is selected from cyano,ethynyl, (1-4C)alkyl, cyclopentyl, cyclohexyl, cyclohexenyl,6,6-dimethyl-bicyclo[3.1.1]hept-2-yl, indanyl optionally substitutedwith methyl, biphenyl, naphthyl, phenyl optionally substituted with one,two or three substituents independently selected from chloro, fluoro,bromo, (1-4C)alkyl, (2-4C)alkynyl, (1-4C)alkoxy, dimethylamino,trifluoromethyl, trifluoromethoxy and (3-6C)cycloalkyl, and R1 isfurther selected from phenyl monosubstituted with phenoxy, benzyl,benzyloxy, phenylethyl, pyrazolyl or triazolyl, and R1 is furtherselected from pyrazolyl, thiazolyl, oxadiazolyl, thienyl,tetrahydrofuranyl, pyridinyl, tetrahydropyranyl, each optionallysubstituted with chloro, (1-4C)alkyl or phenyl substituted with(1-4C)alkyl, and R1 is further selected from indolyl, imidazopyridinyl,dihydrobenzofuranyl and benzdioxanyl each optionally substituted with(1-4C)alkyl. In preferred embodiments, R1 is selected from ethynyl,(1-4C)alkyl, cyclopentyl, cyclohexyl, cyclohexenyl, biphenyl, naphthyl,phenyl optionally substituted with one, two or three substituentsindependently selected from chloro, fluoro, bromo, (1-4C)alkyl,(1-4C)alkoxy, dimethylamino, trifluoromethyl and trifluoromethoxy, andfurther selected from phenyl monosubstituted with phenoxy, benzyl,benzyloxy, phenylethyl, pyrazolyl or triazolyl, and further selectedfrom thiazolyl, thienyl, tetrahydrofuranyl, pyridinyl,tetrahydro-pyranyl, each optionally substituted with chloro or(1-4C)alkyl, and benzdioxanyl. In particular, R1 is selected from(1-4C)alkyl, cyclopentyl, cyclohexyl, pyridinyl and phenyl, wherein thelatter two groups are optionally substituted with one or twosubstituents independently selected from chloro, fluoro, bromo,(1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl. In preferred embodiments,R1 is (1-4C)alkyl or dichlorophenyl.

In a highly preferred embodiment of the invention, R1 is2,6-dichlorophenyl; A is the linking group —Y—(CH₂)_(n)—X—, wherein Y isattached to R1 and is a bond, n is 1 and X is attached to the phenylenegroup and is —O—; R2 is H; R3 is —(CH₂)₂—COOH; and R4 is H.

In further preferred embodiments of the invention, R1 is (1-4C)alkyl; Ais the linking group —Y—(CH₂)_(n)—X—, wherein Y is attached to R1 and isa bond, n is an integer selected from 1 to 6 and X is attached to thephenylene/pyridyl group and is —O— or a bond; R2 is H; R3 is selectedfrom —(CH₂)₂—COOH, —(CH₂)₃—COOH, —CH₂—CHCH₃—COOH, —CH₂—C(CH₃)₂—COOH,—CHCH₃—CH₂—COOH, —(CH₂)₂—PO₃H₂, —(CH₂)₃—PO₃H₂ and —(CH₂)₂—OPO₃H₂; and R4is H. Preferably, R1 and —(CH₂)_(n)— together are a linear octyl group.Further preferred is R3 is —(CH₂)₂—PO₃H₂. In a further preferredembodiment, X is —O—.

The term halogen refers to fluoro, chloro, bromo, or iodo. Preferredhalogens are fluoro and chloro, and in particular chloro.

The term (1-4C)alkyl means a branched or unbranched alkyl group having1-4 carbon atoms, for example methyl, ethyl, propyl, isopropyl andbutyl. A preferred alkyl group is methyl.

The term (1-4C)alkoxy means an alkoxy group having 1-4 carbon atoms,wherein the alkyl moiety is as defined above. A preferred alkoxy groupis methoxy.

The term (1-4C)alkylene means a branched or unbranched alkylene grouphaving 1-4 carbon atoms, for example methylene, —CCH₃CH₂—, and the like.In the definition of R3 which is (1-4C)alkylene-R5, one or more carbonatoms in the alkylene group may (amongst others) independently besubstituted with (CH₂)₂ to form a cyclopropyl moiety, meaning to form aR3 group such as

The term (2-4C)alkynyl means a branched or unbranched alkynyl grouphaving 2-4 carbon atoms, wherein the triple bond may be present atdifferent positions in the group, for example ethynyl, propargyl,1-butynyl, 2-butynyl, etc.

The term (3-6C)cycloalkyl means a cyclic alkyl group having 3-6 carbonatoms, thus cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Preferred are cyclopentyl and cyclohexyl.

The term (4-6C)cycloalkenyl means a cyclic alkenyl group having 4-6carbon atoms and comprising one or two double bonds, for examplecyclohexenyl.

The term (3-6C)cycloalkylene means a cyclic alkyl group having twoattachment points. Preferred is 1,3-cyclobutylene, having the structure

The term (6-8C)bicycloalkyl means a fused ring system of two cycloalkylgroups having together 6-8 carbon atoms, for example the groupbicyclo[3.1.1]hept-2-yl.

The term (8-10C)bicyclic group means a fused ring system of an aromaticand a non-aromatic ring structure having together 8-10 carbon atoms, forexample the indane group.

The term monocyclic heterocycle encompasses monocyclic heteroaryl groupsand non-aromatic heteromonocyclic groups, for example furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, triazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl,morpholinyl, and the like.

The term bicyclic heterocycle encompasses bicyclic heteroaryl groups andnon-aromatic heterobicyclic groups, for example indolyl, indazolyl,isoindolyl, indolizinyl, benzimidazolyl, imidazothiazolyl,imidazopyridinyl, benzfuranyl, dihydrobenzofuranyl, benzdioxanyl,quinolinyl, isoquinolinyl, quinolizinyl, tetrahydroisoquinolinyl, andthe like.

With reference to substituents, the term “independently” means that thesubstituents may be the same or different from each other in the samemolecule.

The compounds of the invention may suitably be prepared by methodsavailable in the art, and as illustrated in the experimental section ofthis description.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. The independentsyntheses of these diastereomers or their chromatographic separationsmay be achieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates which are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography.

Compounds may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, compounds may formsolvates with water (i.e., hydrates) or common organic solvents, andsuch solvates are also intended to be encompassed within the scope ofthis invention.

Isotopically-labeled compound of formula (I) or pharmaceuticallyacceptable salts thereof, including compounds of formula (I)isotopically-labeled to be detectable by PET or SPECT, also fall withinthe scope of the invention. The same applies to compounds of formula (I)labeled with [¹³C]—, [¹⁴C]—, [³H]—, [¹⁸F]-, [¹²⁵I]— or otherisotopically enriched atoms, suitable for receptor binding or metabolismstudies.

The term “pharmaceutically acceptable salt” refers to those salts thatare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. They can be prepared in situwhen isolating and purifying the compounds of the invention, orseparately by reacting them with pharmaceutically acceptable non-toxicbases or acids, including inorganic or organic bases and inorganic ororganic acids.

The compounds of the invention may be administered enterally orparenterally. The exact dose and regimen of these compounds andcompositions thereof will be dependent on the biological activity of thecompound per se, the age, weight and sex of the patient, the needs ofthe individual subject to whom the medicament is administered, thedegree of affliction or need and the judgment of the medicalpractitioner. In general, parenteral administration requires lowerdosages than other methods of administration which are more dependentupon adsorption. However, the dosages for humans are preferably 0.001-10mg per kg body weight. In general, enteral and parenteral dosages willbe in the range of 0.1 to 1,000 mg per day of total active ingredients.

Mixed with pharmaceutically suitable auxiliaries, e.g. as described inthe standard reference “Remington, The Science and Practice of Pharmacy”(21^(st) edition, Lippincott Williams & Wilkins, 2005, see especiallyPart 5: Pharmaceutical Manufacturing) the compounds may be compressedinto solid dosage units, such as pills or tablets, or be processed intocapsules or suppositories. By means of pharmaceutically suitable liquidsthe compounds can also be applied in the form of a solution, suspensionor emulsion.

For making dosage units, e.g. tablets, the use of conventional additivessuch as fillers, colorants, polymeric binders and the like, iscontemplated. In general, any pharmaceutically suitable additive whichdoes not interfere with the function of the active compounds can beused.

Suitable carriers with which the compounds of the invention can beadministered include for instance lactose, starch, cellulose derivativesand the like, or mixtures thereof, used in suitable amounts.Compositions for intravenous administration may for example be solutionsof the compounds of the invention in sterile isotonic aqueous buffer.Where necessary, the intravenous compositions may include for instancesolubilizing agents, stabilizing agents and/or a local anesthetic toease the pain at the site of the injection.

Pharmaceutical compositions of the invention may be formulated for anyroute of administration and comprise at least one compound of thepresent invention and pharmaceutically acceptable salts thereof, withany pharmaceutically suitable ingredient, excipient, carrier, adjuvantor vehicle.

By “pharmaceutically suitable” it is meant that the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In an embodiment of the invention, a pharmaceutical pack or kit isprovided comprising one or more containers filled with one or morepharmaceutical compositions of the invention. Associated with suchcontainer(s) can be various written materials such as instructions foruse, or a notice in the form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals products,which notice reflects approval by the agency of manufacture, use, orsale for human or veterinary administration.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described in this document.

LEGEND TO THE FIGURE

FIG. 1 Percentage of alternation of young and old C57BL/6J male mice inthe T-maze with either vehicle (control groups) or compound 34b (10mg/kg; p.o.)

The following examples are intended to further illustrate the inventionin more detail.

EXAMPLES §1. Materials and Methods

Nuclear magnetic resonance spectra (¹H NMR) were determined in theindicated solvent using a Bruker Avance-I 400 with a 9.4 T magnet (¹H:400 MHz, ¹³C: 100 MHz), equipped with a BBI inversie broadband probeheadwith Z-gradient and ATM, or a Bruker Avance-DRX 600 with a 14.1 Tmagnet, equipped with a TXI inverse triple resonance cryoprobehead withZ-gradient and ATM, at 300 K, unless indicated otherwise. The spectrawere determined in deuterated chloroform (CDCl₃) with 99.8 atom % D; orin dimethylsulfoxide-d₆ (DMSO-d₆) containing 0.03 v/v %tetramethylsilane; both obtained from Aldrich Chemical shifts (δ) aregiven in ppm downfield from tetramethylsilane. Coupling constants J aregiven in Hz. Peakshapes in the NMR spectra are indicated with thesymbols ‘q’ (quartet), ‘dq’ (double quartet), ‘t’ (triplet), ‘dt’(double triplet), ‘d’ (doublet), ‘dd’ (double doublet), ‘s’ (singlet),‘bs’ (broad singlet) and ‘m’ (multiplet). NH and OH signals wereidentified after mixing the sample with a drop of D₂O.

Melting points were recorded on a Büchi B-545 melting point apparatus.

All reactions involving moisture sensitive compounds or conditions werecarried out under an anhydrous nitrogen atmosphere.

Reactions were monitored by using thin-layer chromatography (TLC) onsilica coated plastic sheets (Merck precoated silica gel 60 F254) withthe indicated eluent. Spots were visualised by UV light (254 nm) or l₂.

Liquid Chromatography-Mass Spectrometry (LC-MS) System A:

Column: Acquity UPLC BEH C18 1.7 μm, 50×2.1 mm with 1.7 μm particles.The column is thermo stated in a column oven at 45° C.

Detection: Diode array between 210 and 260 nm

step total time(min) flow (μl/min) A(%) B(%) 0 0 800 95 5 1 0.1 800 95 52 4.5 800 10 90 3 5 800 10 90 4 5.01 800 95 5 A = 99.9% Water with 0.1%CH₃COOH B = 99.9% CH₃CN with 0.1% CH₃COOH

System B:

Column: Waters Sunfire C18, 30×4.6 mm with 2.5 μm particles. The columnis thermo stated in a column oven at 23° C.

Detection: UV/VIS meter with the wavelength set to 254 nm+evaporativelight scattering detector operating at 70° Celsius and 1.7 bar N₂pressure.

step total time (min) flow (ul/min) A(%) B(%) 0 0 1800 95 5 1 1.8 1800 0100 2 2.6 1800 0 100 3 2.8 1800 95 5 4 3.0 1800 95 5 A = 99.9% Waterwith 0.1% HCOOH B = 99.9% CH₃CN with 0.1% HCOOH

The reported retention times (R_(t)), for System B, are for the peak inthe Total Ion Current (TIC) chromatogram which showed the mass for[M+H]+ within 0.5 amu accuracy of the calculated exact MW and had anassociated peak in the Evaporative Light Scattering (ELS) chromatogramwith a relative area % (purity) of >85%.

§2. General Aspects of Syntheses

Suitable syntheses of claimed compounds and intermediates containing2-aryl-morpholine moieties follow routes. 1Scheme see; as describedbelow

Q₁ is a group equal to R1-A, or a group that can be converted to R1-A.Q₂ is a group equal to R3, or a group that can be converted to R3. Fordetails, see the full details given below.

The synthesis begins with a suitably substituted acetophenone (II).Suitably substituted acetophenones are commercially available or can beobtained from other commercially available acetophenones. For example byO-alkylation of (un)substituted 4-hydroxyacetophenones. ThisO-alkylation can be done with a suitable alkylating agent like1-bromooctane or benzyl bromide, in solvents such as dimethylsulfoxide(DMSO), acetone, or acetonitrile, in the presence of a base likepotassium hydroxide or potassium carbonate, at temperatures between 0°C. and 60° C. As another example,1-(4-benzyloxy-3-trifluoromethyl-phenyl)-ethanone was obtained from4′-fluoro-3′-(trifluoromethyl)acetophenone by reaction withbenzylalcohol in the presence of a strong base like potassiumtert-butoxide, in a solvent like tetrahydrofuran, at a temperature ofaround 70° C.

The suitably substituted acetophenone (II) is brominated to afford2′-bromo-acetophenones (III). Bromination can be done with copper(II)bromide in a suitable solvent like ethyl acetate with heating underreflux; via reaction of the corresponding silyl enol ether, preparedwith DI PEA and TMSOTf, at 0° C., with NBS in a solvent likedichloromethane, at room temperature; or with tetra-N-butylammoniumtribromide, in a solvent like methanol, at room temperature.

Reaction of the 2′-bromoacetophenones (III) with benzyl amine, in asolvent like ethanol and chloroform, at temperatures between 0° C. androom temperature, afforded aminoketones (R4=H) which where directlyreduced with a reducing agent like sodium borohydride in a solvent likeethanol and chloroform, at temperatures between 0° C. and roomtemperature, to afford amino alcohols (IV, R4=H). Alternatively,2′-bromoacetophenones (III) can be reduced with a suitable reducingagent like NaBH₄, in a solvent such as 1,4-dioxane, at room temperature,followed by treatment with a base, such as KOH, in a mixture of waterand a suitable solvent, such as Et₂O, to afford 2-aryloxiranes, which ontreatment with benzyl amine at a temperature of 80° C., afford aminoalcohols (IV, R4=H). Another method for the synthesis of aminoalcohols(IV, R4=Me) is by the reaction of a suitably substituted acetophenonewith trimethylsilyl cyanide in the presence of a lewis acid, like zinciodide, at room temperature, in the neat. Followed by reduction of theintermediate cyanohydrin with a reducing agent, like lithium aluminumhydride, in a solvent like tetrahydrofuran, and subsequent imineformation with benzaldehyde in the presence of an acidic catalyst, likep-toluenesulfonic acid, in a solvent such as toluene, and finallyreduction of the intermediate imine with sodium borohydride, in asolvent like methanol, at temperatures between −15° C. and roomtemperature.

The amino alcohols (IV) can be reacted with an activated chloroaceticacid or bromoacetic acid in a solvent such as dichloromethane with abase such as triethylamine, and subsequently cyclized in a solvent suchas 2-propanol with a base such as potassium hydroxide to affordmorpholin-3-ones. Those morpholin-3-ones can then be reduced with areducing agent such as borane in a solvent such as tetrahydrofuran, attemperatures between 0° C. and room temperature, to afford the N-benzylmorpholines (V). Some of the N-benzyl morpholines (V) can be convertedto other N-benzyl morpholines (V), see Scheme 2. For exampleN-benzyl-2-(4-bromophenyl)-morpholine (V-Br) was used as startingmaterial in the following sequences:

Thus, treatment of V-Br with n-butyl lithium at −75° C., in a solventlike tetrahydrofuran or diethyl ether, followed by quenching with aformamide, like N,N-dimethylformamide or N-formylmorpholine, results inthe formation of V-CHO. If the intermediate lithium species is quenchedwith a suitable isocyanate then the corresponding amides V-CONHG areformed.

Reduction of V-CHO, with a reducing agent like sodium borohydride, in asolvent like methanol, at temperatures between 0° C. and roomtemperature, afforded the benzylic alcohols V-CH2OH.

Compounds of type V-CH2OH can be coupled under Mitsunobu conditions withphenols, in a solvent such as tetrahydrofuran or dichloromethane, atroom temperature.

Compounds of type V-CHO may also be coupled with a suitable phosphoniumylid, in a solvent such as tetrahydrofuran at a temperature around 70°C., to afford compounds of type V-CHCHG. The ylid can be generated froma suitable phosphonium salt with a strong base such as sodium hydride ina solvent such as tetrahydrofuran, at temperatures around 0° C.

V-Br could also be converted to V-OH, with a suitable palladiumcatalyst, in a solvent like 1,4-dioxane (Anderson K. W.; Ikawa T.,Tundel R. E., Buchwald S. L. J. Am. Chem. Soc. 2006 128(33),10694-10695). Compounds V-OH can be alkylated, for example underphase-transfer conditions in solvent such as water and 1,4-dioxane, witha base such potassium hydroxide and a phase-transfer catalyst liketetrabutylammonium bromide, at temperatures around the boiling point ofthe solvent.

G is a group that is part of R1-A in the final compounds I.

Under palladium catalysis IV-Br can also be converted to V-CH2G with asuitable organometallic reagent like a boron reagent (Suzuki-reaction),or a zinc reagent (Negishi-reaction), in a solvent like toluene ortetrahydrofuran, at temperatures near the boiling point of the solvent.Also V-Br can be coupled with a suitable amine-donor, like benzophenoneimine, under palladium catalysis in the presence of a base, like sodiumtert-butoxide, in a solvent like toluene at temperatures around 100° C.Subsequent treatment with an aqueous acid, like hydrochloric acid, atroom temperature, leads to intermediates V-NH2. V-NH2 can be reactedwith a suitable alkylating agent and a base likeN-ethyldiisopropylamine, in a solvent like methanol at room temperatureto afford the secondary amines V-NHCH2G. V-NH2 can also be reacted witha suitable acylating reagent like an acyl chloride, with a suitable baselike N-ethyldiisopropylamine, in a solvent like acetonitrile, attemperatures between 0° C. and room temperature to afford the amidesV-NHCOG.

Removal of the N-benzyl group in the N-benzyl morpholines (V), can bedone by hydrogenation in a solvent such as ethanol and a catalyst likepalladium hydroxide, or alternatively by reaction with ACE-Cl in asolvent such as 1,2-dichloroethane, followed by reaction of theintermediate carbamate with methanol. The obtained morpholines (VI) canbe converted to other morpholines (VI) in a sequence of steps. SeeScheme 3. For example, (VI-OH) can be protected at the nitrogen with asuitable protecting group (P.G.M. Wuts, T.W. Greene Protective groups inorganic synthesis, 4th ed., John Wiley & Sons, 2006), such astert-butyloxycarbonyl (BOC), by reaction with di-tert-butyl dicarbonatein a solvent such as acetonitrile at room temperature. Subsequently, thephenolic group can be reacted with a suitable alkylating reagent in asolvent such as acetonitrile, in the presence of a base such aspotassium carbonate, at room temperature. After which thetert-butyloxycarbonyl (BOC) group can be removed by the treatment withan acid, such as hydrogen chloride, in a solvent such as ethanol, attemperatures between room temperature and 60° C., to afford a modifiedmorpholine (VI-OG).

Morpholines (VI) can be reacted with an (meth)acrylic acid ester, in aso called Michael-addition, in a solvent such as acetonitrile, methanol,or N,N-dimethyl-formamide, at temperatures between room temperature and85° C., and eventually with the addition of some base like triethylamineor 1,8-diazabicyclo[5.4.0]undec-7-ene, to affordmorpholin-4-yl-propionic acid esters (Vila, Q2=CH2CH2COOR′). In casethose morpholin-4-yl-propionic acid esters (Vila, Q2=CH2CH2COOR′)contain a phenolic group (VIIa-OH), those compounds can be modified inthe following way: By reaction with a suitable alkylating reagent, suchas a alkyl bromide or an alkyl chloride, in the presence of a base, suchas potassium carbonate or cesium carbonate, in a solvent such asacetonitrile and/or tetrahydrofuran, at room temperature, to affordcompounds of type VIIa-OG. Alternatively, VIIa-OH can be converted toVIIa-OG, by reaction with a suitable alcohol, in the presence oftriphenylphosphine, and a suitable azo-reagent, like diisopropylazodicarboxylate, in a solvent such as tetrahydrofuran ordichloromethane. Furthermore, VII-OH can be converted to thecorresponding trifluoromethanesulfonic acid ester by reaction withN-phenylbis(trifluoromethane-sulfonimide) in the presence of a base,such as Et₃N, in a solvent, such as CHCl₃, at a temperature between roomtemperature 60° C. Those trifluoromethanesulfonic acid ester can than bereacted with thioacetate under palladium catalysis, in a solvent such astoluene, at 110° C., to afford the thioesters VIIa-SAc. Basic hydrolysisof the thioester, with a base such as NaOH, in a solvent such as EtOHand water, at 0° C., followed directly by alkylation with a suitablealkylating agent, at room temperature, affords thioethers VIIa-SG.

Compounds of type VIIa-OG and VIIa-SG can be converted into the finalcompounds I by basic or acidic hydrolysis of the ester, depending on thenature of group E. As an example, tert-butyl esters (E=C(CH₃)₃) can betreated with an acid, such as trifluoroacetic acid or hydrogen chloride,in a solvent such as CH₂Cl₂ or 1,4-dioxane, at room temperature. As afurther example, ethyl esters (E=CH₂CH₃) can be treated with a base,such as sodium hydroxide or lithium hydroxide, in solvents such asethanol, THF, and/or water, at temperatures between room temperature and70° C. Compounds of type VI can also be substituted on nitrogen byreaction with a suitable alkylating reagent like an alkyl bromide oralkyl chloride, in the presence of a base like potassium carbonate,triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, optionally in thepresence of sodium iodide, in a solvent such as acetonitrile or DMF, attemperatures between room temperature and 100° C. Furthermore, compoundsof type VI can also be acylated on nitrogen, with an acid chloride oranother activated acylating reagent, in the presence of a base such asN-ethyldiisopropylamine, in a solvent such as acetonitrile, at roomtemperature.

Compounds of type VI can also be modified on nitrogen with a2,2-difluoro-propionic acid ester group, by the following sequence ofsteps (Cheguillaume A., Lacroix S., Marchand-Brynaert J. TetrahedronLetters 2003, 44, 2375): First reaction with 1H-benzotriazole-1-methanolin a solvent such as ethanol, at temperatures around 50° C.; followed byreaction with a zinc reagent prepared from zinc dust,trimethylsilylchloride and a bromodifluoroacetate, in a solvent such astetrahydrofuran, at temperatures around 70° C.

Morpholines of type VI can also be modified on nitrogen by reaction witha vinyl-phosphonate diester, in a solvent such as acetonitrile attemperatures around 85° C. Compounds of type I wherein R3=(CH₂)₂O PO₃H₂can be synthesized as shown in scheme 4.

Thus a suitable substituted morpholine VI is reacted with2-(2-chloro-ethoxy)tetrahydro-2H-pyran, in the presence of a base, suchas potassium carbonate, and sodium iodide, in a solvent such as DMF, ata temperature around 100° C. The tetrahydro-2H-pyran group is removed bytreatment with an acid such as p-toluenesulfonic acid, in a solvent suchas methanol, at room temperature. The formed alcohol is then treatedwith a phosphoramidite reagent such as di-tert-butylN,N-diisopropylphosphoramidite, in the presence of tetrazole, in amixture of solvents, such as THF, CH₂Cl₂, and CH₃CN, at roomtemperature, and subsequently oxidized with an oxidizing reagent such ashydrogen peroxide or tert-butylhydroperoxide in the same solvents, atroom temperature. Partial hydrolysis of the phosphate esters can be doneunder conditions depending on the nature of the groups E. For exampledi-tert-butyl esters can be hydrolyzed by treatment with an acid, suchas TFA, in a solvent such as CH₂Cl₂, at room temperature. As anotherexample di-ethyl esters can be reacted with bromotrimethylsilane in asolvent such as CH₂Cl₂, at room temperature, followed by treatment withmethanol to affect hydrolysis.

Compounds wherein W is —S—, —SO— or —SO₂— may be prepared as describedbelow and shown in scheme 5.

Q₁ is a group equal to R1-A, or a group that can be converted to R1-A.Q₂ is a group equal to R3, or a group that can be converted to R3. Fordetails, see the full details given below.

The synthesis begins with a suitably substituted bromo-phenyl-aceticacid ester. Suitably substituted bromo-phenyl-acetic acid esters arecommercially available or can be obtained according to methods known inthe literature. The bromo-phenyl-acetic acid ester is reacted with2-aminoethanethiol, in the presence of a base, such as potassiumcarbonate, in a solvent such as ethanol, at room temperature, to obtain2-aryl-thiomorpholin-3-ones (VIII). Those thiomorpholin-3-ones can thenbe reduced with a reducing agent such as borane in a solvent such astetrahydrofuran, at temperatures between 0° C. and room temperature, toafford the 2-aryl-thiomorpholines (IX). Thiomorpholines (IX) can bereacted with an (meth)acrylic acid ester, in a so calledMichael-addition, in a solvent such as acetonitrile, methanol, orN,N-dimethylformamide, at temperatures between room temperature and 85°C., and eventually with the addition of some base like triethylamine or1,8-diazabicyclo[5.4.0]undec-7-ene, to afford morpholin-4-yl-propionicacid esters (X, Q₂=CH2CH2COOR′). In case thosethiomorpholin-4-yl-propionic acid esters (X, Q2=CH2CH2COOR′) aresubstituted with bromine (X, Q1=Br), the bromine can be replaced byiodine (X, Q1=I) in a reaction with sodium iodide, catalysed bycopper(I) iodide, in the presence of N,N-dimethylethylenediamine, in asolvent such as 1,4-dioxane, at temperatures around 130° C., in a closedvessel. Subsequently, the iodine (X, Q1=I), can be substituted by asuitable alcohol, in the presence of a base such as cesium carbonate,and catalyzed by copper(I) iodide and 1,10-phenanthroline, in a solventsuch as toluene, at a temperature around 110° C., to obtain compounds inwhich Q1 is equal to R1-A, and Q2=CH2CH2COOR′. In case R′ is tert-butyl,the ester can be hydrolyzed with acid, such as hydrochloric acid, in asolvent such as 1,4-dioxane, at temperatures between room temperatureand 80° C., to afford compounds (I, W═S). Thiomorpholines (X, W═S,Q1=R1-A, Q2=CH2CH2COOR′), can be oxidized with an oxidizing reagent suchas potassium peroxymonosulfate (Oxone®), in a solvent such asmethanol/water, at temperatures between 0° C. and room temperature toafford the thiomorpholine 1-oxides (X, W═SO, Q1=R1-A, Q2=CH2CH2COOR′).In case R′ is tert-butyl acid hydrolysis as described for thethiomorpholines affords compounds (I, W═SO).

Thiomorpholines (IX) can be protected at the nitrogen with a suitableprotecting group (P.G.M. Wuts, T.W. Greene Protective groups in organicsynthesis, 4th ed., John Wiley & Sons, 2006), such astert-butyloxycarbonyl (BOC), by reaction with di-tert-butyl dicarbonatein a solvent such as acetonitrile at room temperature. Subsequently, thethiomorpholines can be oxidized with an oxidizing reagent such as3-chloroperoxybenzoic acid, in a solvent such as dichloromethane, attemperatures between 0° C. and room temperature, to obtainthiomorpholine 1,1-dioxides (XI). After which the tert-butyloxycarbonyl(BOC) group can be removed by the treatment with an acid, such ashydrogen chloride, in a solvent such as ethanol, at temperatures betweenroom temperature and 60° C., to afford modified thiomorpholine1,1-dioxides (XII). Thiomorpholine 1,1-dioxides can then be reacted in aso called Michael reaction as described above for the thiomorpholines,to obtain compounds XIII (Q2=CH2CH2COOR′). In case compounds XIII aresubstituted with bromine (Q1=Br), they can be substituted by a suitablealcohol, in the presence of a base such as cesium carbonate, andcatalyzed by a palladium catalyst, such as Pd(AcO)₂, and a suitablephosphine ligand, in a solvent such as toluene, at a temperature around100° C., to obtain compounds XIII (W═SO₂, Q1=R1-A, Q2=CH2CH2COOR′). Incase R′ is tert-butyl acid hydrolysis as described for thethiomorpholines affords compounds (I, W═SO₂).

Abbreviations

ACE-Cl 1-Chloroethyl chloroformateAcCl Acetyl chlorideAlCl₃ Aluminum chloride9-BBN 9-borabicyclo[3.3.1]nonane dimerBH₃.THF Borane tetrahydrofuran complexn-BuLi n-Butyl lithiumnBu₄NBr Tetrabutylammonium chloride

CHCl₃ Chloroform CH₂Cl₂ Dichloromethane CH₃CN Acetonitrile

Cs₂CO₃ Cesium carbonateCuBr₂ Copper(II) bromideCuI Copper(I) iodideDBU 1,8-Diazabicyclo[5.4.0]undec-7-eneDIAD Diisopropyl azodicarboxylate

DIPEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide

DMSO Dimethyl sulfoxide

Et₃N Triethylamine

Et₂O Diethyl ether

EtOH Ethanol

EtOAc Ethyl acetateHCl Hydrogen chlorideH₂SO₄ Sulfuric acidK₂CO₃ Potassium carbonateKHCO₃ Potassium bicarbonateKI Potassium iodideKOH Potassium hydroxideKOtBu Potassium tert-butoxideLiAlH₄ Lithium aluminum hydrideLiHMDS Lithium bis(trimethylsilyl)amideLiOH Lithium hydroxideMeI Methyl iodideMeMgBr Methylmagnesium bromide

MeOH Methanol

min. minutesNaBH₄ Sodium borohydrideNaHCO₃ Sodium bicarbonateNaI Sodium iodideNaN₃ Sodium azideNaOH Sodium hydroxideNaOtBu Sodium tert-butoxideNa₂SO₄ Sodium sulfate

NBS N-Bromosuccinimide

PBr₃ Phosphorus tribromidePd₂dba₃ Tris(dibenzylideneacetone)dipalladium(0)Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)PdCl₂(PPh₃)₂ Bis(triphenylphosphine)palladium(II) dichloride

Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)

iPr₂O Diisopropyl ether

RT Room Temperature SiO₂ Silica gel

TFA Trifluoroacetic acid

THF Tetrahydrofuran TMSCl Chlorotrimethylsilane

TMSOTf Trimethylsilyl trifluoromethanesulfonatep-TsOH p-Toluenesulfonic acid monohydrateZrCl4 Zirconium tetrachloride

§3. Syntheses of Intermediates Aryl(Thio)Morpholines

1-(4-Octyloxy-phenyl)-ethanone

To a solution of 4′-hydroxyacetophenone (25.0 g; 183.6 mmol) in DMSO(300. mL) was added KOH (11.3 g; 201.9 mmol.) and the reaction mixturewas stirred for 1 hour at RT. After 1 hour the reaction mixture wascooled (0° C.) and 1-bromooctane (34.9 mL; 201.9 mmol) was added. Theice bath was removed and the reaction mixture was stirred overnight atRT. The reaction mixture was extracted with EtOAc/5% aqueous NaHCO₃solution. The organic layer was dried with Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography (SiO₂,Et₂O:hexanes 1:3) to afford 1-(4-octyloxy-phenyl)-ethanone (43.08 g)

1-(4-benzyloxy-2-methyl phenyl)-ethanone

A mixture of 4′-hydroxy-2′-methylacetophenone (24.88 g; 165.7 mmol)), KI(5.50 g; 33.1 mmol), K₂CO₃ (34.3 g; 248.5 mmol) and benzyl bromide (21.7mL; 182.2 mmol) in acetone (200 mL) was stirred overnight at RT.Subsequently the resulting mixture was filtered and partitioned betweenEtOAc and 5% aqueous NaHCO₃. The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo to afford1-(4-benzyloxy-2-methylphenyl)-ethanone, which was used as such.

1-(4-benzyloxy-3-methylphenyl)-ethanone

A mixture of 4′-hydroxy-3′-methylacetophenone (10.00 g; 66.6 mmol) andK₂CO₃ (13.80 g; 99.9 mmol) in acetone (100 mL) was stirred, at RT for 40minutes. Subsequently, benzyl bromide (7.9 mL; 66.6 mmol) was added andthe resulting mixture was heated under reflux for 2.5 h. After coolingto RT the mixture was concentrated in vacuo. The residue was dissolvedin EtOAc, washed with 5% aqueous ammonia, water, and brine, dried(MgSO₄), filtered and concentrated in vacuo to afford1-(4-benzyloxy-3-methylphenyl)-ethanone (15.86 g).

The following compound was obtained according to a similar manner:

-   1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone

1-(4-Benzyloxy-3-trifluoromethyl-phenyl)-ethanone

A mixture of benzyl alcohol (10.9 mL; 104.98 mmol) and KOtBu (12.96 g;115.5 mmol) in THF (500 mL) was heated under reflux for 10 minutes.Subsequently, 4′-fluoro-3′-(trifluoromethyl)acetophenone (21.64 g; 105mmol) was added and the mixture heated under reflux for another 2 hours.After cooling to RT, the mixture was partitioned between EtOAc and a 5%aqueous NaHCO₃ solution. The organic layer was separated, dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, Et₂O:hexanes 1:2.5) to afford1-(4-Benzyloxy-3-trifluoromethyl-phenyl)-ethanone (22.37 g).

Methanesulfonic acid 4-acetyl-3-trifluoromethyl-phenyl ester

To a solution of 1-(4-hydroxy-2-trifluoromethyl-phenyl)-ethanone (29.74g; 145.7 mmol) in CH₂Cl₂ (300 mL) and THF (120 mL) was added Et₃N (24.4mL; 174.8 mmol), at 0° C. To the resulting mixture was added dropwise asolution of methanesulfonyl chloride (12.5 mL; 160.3 mmol) in CH₂Cl₂ (60mL), at 0° C. Subsequently the mixture was stirred overnight at RT, andpoured in ice-water. The layers were separated and the organic layer waswashed with 1 M aqueous HCl and water; dried (MgSO₄), filtered andconcentrated in vacuo to afford methanesulfonic acid4-acetyl-3-trifluoromethyl-phenyl ester (40.47 g), which was used assuch.

The following compounds were prepared in an analogues manner:

-   Methanesulfonic acid 4-acetyl-2-chloro-phenyl ester-   Methanesulfonic acid 4-acetyl-3-fluoro-phenyl ester

1-(2-Chloro-4-methoxy-phenyl)-ethanone

To a mixture of AlCl₃ (42.08 g; 315.60 mmol) in CH₂Cl₂ (300 mL) wasadded dropwise 3-chloroanisole (22.50 g; 157.80 mmol), at −30° C. To theresulting mixture was added dropwise a solution of AcCl (10.50 mL;147.63 mmol) in CH₂Cl₂ (100 mL) at such a rate to keep the temperaturebelow −15° C. The resulting mixture was stirred for 4 hours at −10° C.Subsequently, the mixture was poured onto ice and extracted with CH₂Cl₂.The combined organic layers, were dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, Et₂O/hexanes 1:9) to afford1-(2-chloro-4-methoxy-phenyl)-ethanone (17.68 g).

2-Bromo-1-(4-octyloxy-phenyl)-ethanone

To a solution of 1-(4-octyloxy-phenyl)-ethanone (43.0 g; 173.1 mmol) inEtOAc (200 mL) was added CuBr₂ (77.3 g; 346.2 mmol) and heated to refluxfor 2 hours. The reaction mixture was filtered over Kieselguhr. Thereaction mixture was washed with 10% aqueous solution of Sodiumthiosulfate and brine. The organic layer was dried over Na₂SO₄,concentrated in vacuo and purified by column chromatography (SiO₂,Et₂O:hexanes 1:7)) to afford 2-bromo-1-(4-octyloxy-phenyl)-ethanone(36.3 g)

1-(4-Benzyloxy-2-methyl-phenyl)-2-bromo-ethanone

To a solution of 1-(4-benzyloxy-2-methylphenyl)-ethanone (42.00 g; 174.8mmol) in MeOH (300 mL) was added tetra-N-butylammonium tribromide (84.28g; 174.8 mmol) and the mixture was stirred overnight at RT.Subsequently, the MeOH was evaporated in vacuo, and the residuepartitioned between EtOAc (300 mL) and 5% aqueous NaHCO₃. The organiclayer was dried (Na₂SO₄), filtered, concentrated in vacuo and purifiedby column chromatography (SiO₂, Et₂O:hexanes 1:1) to afford1-(4-benzyloxy-2-methyl-phenyl)-2-bromo-ethanone (49.93 g).

The following compound was obtained according to a similar manner:

-   1-(4-Benzyloxy-3-trifluoromethyl-phenyl)-2-bromo-ethanone

1-(4-Benzyloxy-3-methyl-phenyl)-2-bromo-ethanone

To a solution of 1-(4-benzyloxy-3-methyl-phenyl)-ethanone (12.89 g; 53.1mmol) in CH₂Cl₂ was added, dropwise, at 0° C., DIPEA (10.9 mL; 63.7mmol) and trimethylsilyl trifluoromethanesulfonate (11.1 mL; 61.1 mmol).The resulting mixture was stirred at 0° C. for 1 hour, and subsequently,NBS (10.87 g; 61.1 mmol) was added in one portion. The mixture wasallowed to warm to RT stirred overnight. Then the mixture wasconcentrated in vacuo, the residue dissolved in EtOAc, washed with watertwice, and brine, dried (MgSO₄), filtered, and concentrated in vacuo toafford 1-(4-benzyloxy-3-methyl-phenyl)-2-bromo-ethanone (11.90 g).

The following compound was obtained according to a similar manner:

-   1-(4-Benzyloxy-3-methoxy-phenyl)-2-bromo-ethanone-   Methanesulfonic acid 4-(2-bromo-acetyl)-3-trifluoromethyl-phenyl    ester-   Methanesulfonic acid 4-(2-bromo-acetyl)-2-chloro-phenyl ester-   Methanesulfonic acid 4-(2-bromo-acetyl)-3-fluoro-phenyl ester-   1-(3-Benzyloxy-phenyl)-2-bromo-ethanone-   2-Bromo-1-(2-chloro-4-methoxy-phenyl)-ethanone-   2-Bromo-1-(5-bromo-pyridin-2-yl)-ethanone

2-Azido-1-(4-benzyloxy-phenyl)-ethanone

To a mixture of 1-(4-benzyloxy-phenyl)-2-bromo-ethanone (28.55 g; 93.6mmol) in CH₂Cl₂ (300 mL) and water (30 mL) was added nBu₄NBr (1.51 g;4.7 mmol) and NaN₃ (6.69 g; 102.9 mmol) in one portion. After 4 h at RT,the layers were separated. The organic layer was washed water, dried(Na₂SO₄), filtered and concentrated in vacuo to afford2-azido-1-(4-benzyloxy-phenyl)-ethanone (23.64 g).

Methanesulfonic acid 4-oxiranyl-3-trifluoromethyl-phenyl ester

To a solution of methanesulfonic acid4-(2-bromo-acetyl)-3-trifluoromethyl-phenyl ester (33.95 g; 89.3 mmol)in 1,4-dioxane (150 mL) was added dropwise a solution of NaBH₄ (2.37 g;62.5 mmol) in water (47 mL). The resulting mixture was stirred at RT for2.5 hours, subsequently, quenched with 0.5M aqueous HCl (125 mL), andextracted with EtOAc. The combined organic layers were washed withwater, dried (MgSO₄), filtered and concentrated in vacuo. The residuewas dissolved in Et₂O (500 mL) and treated with a solution of KOH (4.19g; 74.7 mmol) in water (100 mL). The resulting mixture was heated underreflux for 4 hours. After cooling to RT, the volatiles were removed invacuo and the residue was partitioned between EtOAc and water. Theorganic layer was washed with water, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by column chromatography(CH₂Cl₂) to afford methanesulfonic acid4-oxiranyl-3-trifluoromethyl-phenyl ester (23.54 g).

The following compounds were prepared in an analogues manner:

-   Methanesulfonic acid 4-oxiranyl-3-fluoro-phenyl ester-   Methanesulfonic acid 4-oxiranyl-2-chloro-phenyl ester-   2-(2-Chloro-4-methoxy-phenyl)-oxirane

2-Amino-1-(4-benzyloxy-phenyl)-ethanol

To a suspension of LiAlH₄ (8.18 g; 215.6 mmol) in THF (100 mL), wasadded dropwise a solution of 2-azido-1-(4-benzyloxy-phenyl)-ethanone(23.05 g; 86.2 mmol) in THF (200 mL), at 0° C. The mixture was stirredat 0° C. for 20 min. and subsequently 2 hours at RT. Thereafter, water(50 mL), and 2M aqueous NaOH-solution (150 mL) were added consecutively.The formed precipitate was removed by filtration over kieselguhr, andwashed with MeOH. The filtrate was concentrated in vacuo and theremaining aqueous layer was extracted with CH₂Cl₂. The combined organiclayers were dried (Na₂SO₄), filtered and concentrated in vacuo to afford2-amino-1-(4-benzyloxy-phenyl)-ethanol (20.10 g)

2-Benzylamino-1-(4-octyloxy-phenyl)-ethanol

To a cooled (0° C.) suspension of 2-Bromo-1-(4-octyloxy-phenyl)-ethanone(36.1 g; 110.3 mmol) in EtOH (500 mL) and CHCl₃ (100 mL) was addedbenzylamine (48.2 mL; 441.2 mmol). After 30 minutes the ice-bath wasremoved and the mixture stirred for another 2 hours at RT. Subsequentlythe reaction mixture was cooled again to 0° C. and NaBH₄ (6.26 g; 165.5mmol) was added in small portions. The resulting mixture was stirred at0° C. for 1 hour and thereafter another 4 hours at RT. The reactionmixture was quenched with 1M aqueous HCl (750 mL) at 0° C. and stirredat RT for 1 hour. The reaction mixture was concentrated in vacuo and theresidue was partitioned between EtOAc and 2 N aqueous NaOH. The organiclayer was dried (Na₂SO₄), filtered, concentrated in vacuo, and purifiedby column chromatography (SiO₂, EtOAc) to give2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22.58 g)

The following compounds were obtained according to a similar manner:

-   2-Benzyl amino-1-(4-bromo-phenyl)-ethanol-   2-Benzyl amino-1-(4-benzyloxy-phenyl)-ethanol-   2-Benzyl amino-1-(4-benzyloxy-2-methyl-phenyl)-ethanol-   2-Benzyl amino-1-(4-benzyloxy-3-methyl-phenyl)-ethanol-   2-Benzyl amino-1-(4-benzyloxy-3-trifluoromethyl-phenyl)-ethanol-   2-Benzyl amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethanol    2-Benzylamino-1-(3-benzyloxy-phenyl)-ethanol-   2-(Benzhydryl-amino)-1-(5-bromo-pyridin-2-yl)-ethanol

Methanesulfonic acid4-(2-benzylamino-1-hydroxy-ethyl)-3-trifluoromethyl-phenyl ester

Methanesulfonic acid 4-oxiranyl-3-trifluoromethyl-phenyl ester (23.54 g;79.2 mmol) was dissolved in benzylamine (26 mL). The resulting mixturewas stirred at 80° C. for 4 h. After cooling to RT, Et₂O was added andthe mixture cooled to 0° C. The formed precipitate was collected byfiltration, washed with Et₂O, and dried under vacuum, at 40° C., toafford methanesulfonic acid4-(2-benzylamino-1-hydroxy-ethyl)-3-trifluoromethyl-phenyl ester as awhite solid (26.87 g) which was used as such.

The following compounds were prepared in a similar manner:

-   Methanesulfonic acid    4-(2-benzylamino-1-hydroxy-ethyl)-3-fluoro-phenyl ester-   Methanesulfonic acid    4-(2-benzylamino-1-hydroxy-ethyl)-2-chloro-phenyl ester-   2-Benzylamino-1-(2-chloro-4-methoxy-phenyl)-ethanol

1-Amino-2-(4-benzyloxy-phenyl)-propan-2-01

A mixture of 1-(4-benzyloxy-phenyl)-ethanone (18.50 g; 81.8 mmol), zinciodide (0.52 g; 1.6 mmol), and trimethylsilyl cyanide (33.8 mL; 269.8mmol) was stirred overnight at RT. Subsequently, the excesstrimethylsilyl cyanide was removed in vacuo, and the residue dissolvedin THF (100 mL). The resulting solution was added, dropwise, to amixture of lithium aluminum hydride (12.7 g; 335.2 mmol) in THF (200mL). The resulting mixture was heated under reflux for 2 h. Next, themixture was cooled to 0° C. and treated successively with water (13 mL),2M aqueous NaOH (26 mL), and water (13 mL). Thereafter the mixture washeated under reflux for 15 minutes, cooled again to RT, filtered overKieselguhr, and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, MeOH) to afford1-Amino-2-(4-benzyloxy-phenyl)-propan-2-ol (18.15 g).

1-Benzylamino-2-(4-benzyloxy-phenyl)-propan-2-ol

A mixture of 1-amino-2-(4-benzyloxy-phenyl)-propan-2-ol (1.26 g; 4.9mmol), benzaldehyde (0.55 mL; 5.4 mmol), and p-toluenesulfonic acid(0.04 g; 0.24 mmol) in toluene (30 mL) was heated under reflux in aDean-Stark apparatus, overnight. Subsequently, the mixture was cooled toRT and the solvent was removed in vacuo. The residue was suspended inMeOH (30 mL), cooled to −15° C., and treated with NaBH₄ (0.74 g; 19.6mmol), portionwise. After the addition was complete the mixture waswarmed to RT and stirred for one hour. Subsequently, the MeOH wasremoved in vacuo. The residue was partitioned between Et₂O and 5%aqueous NaHCO₃. The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, Et₂O:hexanes 2:1) to give1-benzylamino-2-(4-benzyloxy-phenyl)-propan-2-ol (1.07 g).

4-Benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one

To a solution of 2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22.50 g;63.3 mmol) and Et₃N (9.7 mL; 69.6 mmol) in CH₂Cl₂ (500 mL) was addeddropwise a solution of chloroacetyl chloride (5.5 mL; 69.6 mmol) inCH₂Cl₂ (25 mL), at 0° C. After 1 hour at 0° C. the reaction mixture wasquenched with 1M aqueous HCl (200 mL). The layers were separated and theorganic layer washed with a 5% aqueous NaHCO₃ solution, dried (Na₂SO₄)and concentrated in vacuo. The residue was dissolved in 2-propanol (250mL) and KOH (4.26 g; 76 mmol) was added. The resulting mixture wasstirred at RT for 1 hour and subsequently concentrated in vacuo. Thecrude product was partitioned between EtOAc and 0.5 M aqueous HCl. Thelayers were separated and the organic layer was washed with 5% aqueousNaHCO₃ solution, dried (Na₂SO₄) and evaporated in vacuo to afford4-benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one (22.30 g) which was usedas such in the next step.

The following compounds were obtained according to a similar manner:

-   4-Benzyl-6-(4-bromo-phenyl)-morpholin-3-one-   4-Benzyl-6-(4-benzyloxy-phenyl)-morpholin-3-one-   4-Benzyl-6-(4-benzyloxy-2-methyl-phenyl)-morpholin-3-one-   4-Benzyl-6-(4-benzyloxy-3-methyl-phenyl)-morpholin-3-one-   4-Benzyl-6-(4-benzyloxy-3-methoxy-phenyl)-morpholin-3-one-   4-Benzyl-6-(4-benzyloxy-3-trifluoromethyl-phenyl)-morpholin-3-one-   4-Benzyl-6-(4-benzyloxy-phenyl)-6-methyl-morpholin-3-one-   4-Benzyl-6-(3-benzyloxy-phenyl)-morpholin-3-one-   4-Benzyl-6-(2-chloro-4-methoxy-phenyl)-morpholin-3-one-   4-Benzhydryl-6-(5-bromo-pyridin-2-yl)-morpholin-3-one

The following compounds were obtained according to a similar manner frommethanesulfonic acid phenyl esters using 2.5 equivalents of KOH insteadof 1.25 equivalents.

-   4-Benzyl-6-(4-hydroxy-2-trifluoromethyl-phenyl)-morpholin-3-one-   4-Benzyl-6-(2-fluoro-4-hydroxy-phenyl)-morpholin-3-one-   4-Benzyl-6-(3-chloro-4-hydroxy-phenyl)-morpholin-3-one

N-[2-(4-Benzyloxy-phenyl)-2-hydroxy-ethyl]-2-chloro-acetamide

To a mixture of 2-amino-1-(4-benzyloxy-phenyl)-ethanol (20.10 g; 82.6mmol), Et₃N (13.82 mL; 99.1 mmol), CH₂Cl₂ (200 mL) and MeOH (20 mL) wasadded dropwise chloroacetyl chloride (7.24 mL; 90.9 mmol) at −10° C. Theresulting mixture was allowed to warm to RT and stirred overnight, andsubsequently concentrated in vacuo. The residue was purified by flashchromatography (SiO₂, EtOAc) to affordN-[2-(4-benzyloxy-phenyl)-2-hydroxy-ethyl]-2-chloro-acetamide (17.45 g).

6-(4-Benzyloxy-phenyl)-morpholin-3-one

To a solution of KOtBu (6.68 g; 59.5 mmol) in 2-methyl-2-butanol (100mL) was added dropwise a solution ofN-[2-(4-benzyloxy-phenyl)-2-hydroxy-ethyl]-2-chloro-acetamide (17.30 g;54.1 mmol) in THF (100 mL). The resulting mixture was stirred for 1 hourat RT and then concentrated in vacuo. The residue was dissolved inCH₂Cl₂ and treated with a 1M aqueous solution of HCl, at 0° C. Thelayers were separated and the aqueous layer extracted with CH₂Cl₂. Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedin vacuo to afford 6-(4-benzyloxy-phenyl)-morpholin-3-one (14.10 g).

4-Benzyl-6-(4-benzyloxy-phenyl)-2,2-dimethyl-morpholin-3-one and4-Benzyl-6-(4-benzyloxy-phenyl)-2-methyl-morpholin-3-one

To a solution of 4-benzyl-6-(4-benzyloxy-phenyl)-morpholin-3-one (6.90g; 18.5 mmol) in THF (100 mL) was added dropwise a solution of LiHMDS inTHF (18.5 mL; 1.00 mol/l; 18.5 mmol), at −78° C. The resulting mixturewas stirred at −78° C. for 15 minutes, subsequently, MeI (1.15 mL; 18.5mmol) was added, and the resulting mixture stirred for 1 hour at −78° C.The sequence of addition of LiHMDS and MeI, was repeated three times.After the last addition of MeI the mixture was allowed to warm to RT andstirred overnight. Then an 5% aqueous NaHCO₃ solution was added en themixture extracted with EtOAc. The combined organic layers were dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, Et₂O/hexanes 1:1) to afford twocompounds. The least polar compound was4-benzyl-6-(4-benzyloxy-phenyl)-2,2-dimethyl-morpholin-3-one (1.90 g),and the most polar compound was4-benzyl-6-(4-benzyloxy-phenyl)-2-methyl-morpholin-3-one (3.81 g).

2-(4-Bromo-phenyl)-thiomorpholin-3-one

To a solution of 2-aminoethanethiol hydrochloride (6.93 g; 61 mmol) inEtOH (400 mL) was added K₂CO₃ (16.86 g; 122 mmol), at RT, followed after15 minutes by bromo-(4-bromo-phenyl)-acetic acid ethyl ester (12 mL; 61mmol). The resulting mixture was stirred at RT for two days,subsequently, water was added and the resulting mixture was extractedwith EtOAc. The combined organic layers were dried (MgSO₄), filtered,and concentrated in vacuo. The residue was recrystallized from EtOH toafford 2-(4-bromo-phenyl)-10 thiomorpholin-3-one (12.8 g).

4-Benzyl-2-(4-octyloxy-phenyl)-morpholine

To a solution of 4-benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one (22.22g; 56.2 mmol) in THF (400 mL) was added borane-THF complex (1M, 140.4mL; 140.4 mmol) dropwise, at 0° C. After 1 hour the mixture was allowedto warm to RT and stirred for another 2 hours. To the reaction mixturewas added MeOH (30 mL), at 0° C., and the resulting mixture was stirredat RT for 30 minutes, and subsequently concentrated in vacuo. Theresidue was suspended in MeOH (300 mL.) and 1 M aqueous NaOH (112 mL)was added and heated under reflux for 1 hour. The resulting mixture wasconcentrated in vacuo and the residue was partitioned between EtOAc and5% aqueous NaHCO₃-solution. The organic layer was dried (Na₂SO₄),filtered, and concentrated in vacuo to afford4-benzyl-2-(4-octyloxy-phenyl)-morpholine (20.33 g), which was used assuch in the next step.

The following compounds were obtained according to a similar manner:

-   4-Benzyl-6-(4-bromo-phenyl)-morpholine-   4-Benzyl-2-(4-benzyloxy-phenyl)-morpholine-   4-Benzyl-2-(4-benzyloxy-2-methyl-phenyl)-morpholine-   4-Benzyl-2-(4-benzyloxy-3-methyl-phenyl)-morpholine-   4-Benzyl-2-(4-benzyloxy-3-methoxy-phenyl)-morpholine-   4-Benzyl-2-(4-benzyloxy-3-trifluoromethyl-phenyl)-morpholine-   4-Benzyl-2-(4-benzyloxy-phenyl)-2-methyl-morpholine-   4-Benzyl-6-(4-benzyloxy-phenyl)-2,2-dimethyl-morpholine-   4-Benzhydryl-2-(5-bromo-pyridin-2-yl)-morpholine

4-(4-Benzyl-morpholin-2-yl)-3-trifluoromethyl-phenol

To a solution of4-benzyl-6-(4-hydroxy-2-trifluoromethyl-phenyl)-morpholin-3-one (26.18g; 67.3 mmol) in THF (600 mL) was added dropwise BH₃-THF in THF (235.4mL; 1.00 mol/l; 235.4 mmol), at 0° C. The resulting mixture was stirredfor 1 hour at 0° C. and thereafter 18 hours at RT. Subsequently, 1Maqueous HCl (550 mL) was added and the mixture stirred overnight at RT.The resulting mixture was partitioned between EtOAc and 2M aqueous NaOH(350 mL), the organic layers was dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, CH₂Cl₂/MeOH 98:2) to afford4-(4-benzyl-morpholin-2-yl)-3-trifluoromethyl-phenol

The following compounds were obtained according to a similar manner:

-   4-(4-Benzyl-morpholin-2-yl)-3-fluoro-phenol-   4-Benzyl-2-(3-benzyloxy-phenyl)-morpholine-   4-Benzyl-2-(2-chloro-4-methoxy-phenyl)-morpholine-   2-(4-Bromo-phenyl)-thiomorpholine

4-(4-Benzyl-morpholin-2-yl)-2-chloro-phenol

To a solution of 4-benzyl-6-(3-chloro-4-hydroxy-phenyl)-morpholin-3-one(13.05 g; 39.0 mmol) in THF (600 mL) was added portionwise LiAlH₄ (4.44g; 117.04 mmol) at 0° C. The resulting mixtures was allowed to warm toRT and stirred overnight. Subsequently, the mixture was cooled to 0° C.,and water (4.5 mL), a 2M aqueous NaOH-solution (9.0 mL) and water (9.0mL) were added consecutively. Thereafter the mixture was stirred for 1h. The formed precipitate was removed by filtration over kieselguhr, andwashed with EtOAc. The organic solution was concentrated in vacuo, andthe residue purified by column chromatography (SiO₂, CH₂Cl₂/MeOH 98:2)to afford 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (9.10 g)

4-(4-Benzyl-morpholin-2-yl)-3-chloro-phenol

To a solution of 1 dodecanethiol (12.7 mL; 52.86 mmol) in dry DMF (50mL), was added KOtBu (5.93 g; 52.86 mmol) at 0° C. After completeaddition the mixture was allowed to slowly come to RT (˜30 min), andthen 4-benzyl-2-(2-chloro-4-methoxy-phenyl)-morpholine (5.60 g; 17.62mmol) was added. The resulting mixture was stirred at 110° C. for 6hours. After cooling to RT, EtOAc was added and the resulting mixturewas washed with 5% aqueous NaHCO₃, water and brine; dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, CH₂CL₂/MeOH 99:1) to afford4-(4-benzyl-morpholin-2-yl)-3-chloro-phenol (4.56 g)

4-Benzyl-2-(4-benzyloxy-phenyl)-5,5-dimethyl-morpholine

To a solution of 4-benzyl-6-(4-benzyloxy-phenyl)-morpholin-3-one (7.14g; 19.1 mmol) in THF (100 mL) was added ZrCl₄ (4.46 g; 19.1 mmol), at−10° C. The resulting mixture was stirred for 30 min. at −10° C.,subsequently, a solution of MeMgBr in Et₂O (38.2 mL; 3.00 mol/1; 114.6mmol) was added dropwise, keeping the temperature below 10° C. Aftercomplete addition the resulting mixture was stirred at RT for 1 hour.After cooling the mixture to 0° C. a 2M aqueous NaOH solution was addeddropwise. The resulting suspension was filtered and the filtrate wasextracted three times with CH₂Cl₂. The combined organic layers weredried (Na₂SO₄), filtered, and concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, Et₂O/hexanes 1:3) to afford4-benzyl-2-(4-benzyloxy-phenyl)-5,5-dimethyl-morpholine (3.6 g).

4-(4-Benzyl-morpholin-2-yl)-phenol

To a suspension of 4-benzyl-6-(4-bromo-phenyl)-morpholine (8.70 g; 26.19mmol) in water (25 mL) and 1,4-dioxane (25 mL) was added KOH (3.23 g;57.61 mmol), tris(dibenzylideneaceton)dipalladium(0) (479.6 mg; 0.52mmol) and di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane(444.8 mg; 1.05 mmol). The resulting mixture was heated under reflux fortwo hours. After cooling to RT the reaction mixture was concentrated invacuo. The residue was partitioned between EtOAc and 5% aqueous NaHCO₃solution. The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, Et2O:hexanes 1:1) to afford 4-(4-benzyl-morpholin-2-yl)-phenol(3.67 g).

6-(4-Benzhydryl-morpholin-2-yl)-pyridin-3-ol was made by a similarmethod.

4-Benzyl-2-(4-hexyloxy-phenyl)-morpholine

To a mixture of 4-(4-benzyl-morpholin-2-yl)-phenol (1.33 g; 4.94 mmol)in water (10 mL) and 1,4-dioxane (10 mL) was added KOH (0.55 g; 9.88mmol), 1-bromohexane (1.04 mL; 7.41 mmol) and tetrabutylammonium bromide(0.16 g; 0.49 mmol), the resulting mixture was heated under refluxovernight. After cooling to RT the mixture was concentrated in vacuo,and partitioned between EtOAc and 5% aqueous NaHCO₃solution. The organiclayer was dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, Et2O: hexanes 1:1)to afford 4-benzyl-2-(4-hexyloxy-phenyl)-morpholine (1.31 g).

4-Benzyl-2-(4-heptyloxy-phenyl)-morpholine was obtained according to asimilar manner.

4-Benzyl-2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine

A mixture of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56mmol), 2,6-dichlorobenzyl bromide (0.39 g; 1.64 mmol) and Cs₂CO₃ (2.55g; 7.82 mmol) in CH₃CN (20 mL) was heated under reflux overnight. Aftercooling to RT the resulting mixture was partitioned between EtOAc andwater. The layers were separated and the organic layer, dried (MgSO₄),filtered, and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, CH₂Cl₂:MeOH 98:2) to afford4-benzyl-2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.74g)

The following compounds were obtained according to a similar manner:

-   4-Benzyl-2-[3-chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholine-   4-Benzyl-2-[3-chloro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine

4-Benzyl-2-(4-octyl-phenyl)-morpholine

To a solution of 1-octene (2.12 mL, 13.5 mmol) in THF (50 mL) was added9-BBN (4.3 g, 17.6 mmol), at 0° C. The reaction mixture was allowed towarm to RT and stirred overnight. Subsequently, K₃PO₄ (7.6 g, 35.8 mmol)was added, followed, after 45 minutes, by4-benzyl-6-(4-bromo-phenyl)-morpholine (3.0 g, 9 mmol), palladium(II)acetate (80 mg; 4 mol %), anddicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (296 mg; 8 mol%). The resulting mixture was heated under reflux for 2 hours. Aftercooling to RT the mixture was concentrated in vacuo, the residuedissolved in EtOAc, and washed with 5% aqueous NaHCO₃ solution. Theorganic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo.The residue was purified by column chromatography (SiO₂, Et₂O:hexanes,1:1) to afford 4-benzyl-2-(4-octyl-phenyl)-morpholine (2.58 g).

4-(4-Benzyl-morpholin-2-yl)-benzaldehyde

To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (1.73 g; 5.21mmol) in THF (25 mL) was added dropwise n-BuLi (2.08 mL; 2.50 mol/l;5.21 mmol), at −78° C. The resulting mixture was stirred for one hour,and subsequently a solution of N-formylmorpholine (0.90 g; 7.81 mmol) inTHF (5 mL) was added dropwise, at −78° C. The reaction was quenched bythe addition of an 5% aqueous NaHCO₃ solution, at −70° C. The resultingmixture was extracted with Et₂O. The combined organic layers were dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, Et2O: hexanes 1:1) to afford4-(4-benzyl-morpholin-2-yl)-benzaldehyde (1.21 g).

[4-(4-Benzyl-morpholin-2-yl)-phenyl]-methanol

To a solution of 4-(4-benzyl-morpholin-2-yl)-benzaldehyde (1.19 g; 4.23mmol) in MeOH (25 mL) was added NaBH₄ (0.16 g; 4.23 mmol), in smallportions, at 0° C. After the addition was complete the mixture wasallowed to warm to RT and stirred for one hour. Subsequently, themixture was cooled to 0° C., water was added, and the MeOH evaporated invacuo. To the aqueous solution was added a 5% aqueous NaHCO₃ solutionand EtOAc. The layers were separated and the organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo to afford[4-(4-benzyl-morpholin-2-yl)-phenyl]-methanol (1.16 g) which was used assuch.

4-Benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine

To a solution of 2,6-dichlorophenol (0.68 g; 4.19 mmol) in THF (20 mL)was added DIAD (1.13 mL; 5.72 mmol), and triphenylphosphine (1.50 g;5.72 mmol), at RT, followed, after 30 minutes, by[4-(4-benzyl-morpholin-2-yl)-phenyl]-methanol (1.08 g; 3.81 mmol).Subsequently, the resulting mixture was stirred at RT for 1 hour, andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, Et₂O:hexanes 1:1) to afford4-benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine (2.35 g)which was used as such in the next step.

The following compound was obtained according to a similar manner:

-   4-Benzyl-2-[2-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine

4-(4-Benzyl-morpholin-2-yl)-N-(2,6-dichloro-phenyl)-benzamide

To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (1.01 g; 3.04mmol) in THF (25 mL) was added dropwise n-BuLi (1.2 mL; 2.5 mol/l inhexanes; 3.04 mmol), at −78° C. After 1 hour at −78° C., a solution of2,6-dichlorophenyl isocyanate (0.63 g; 3.34 mmol) in THF (5 mL) wasadded dropwise. The mixture was allowed to warm to RT and then 5%aqueous NaHCO₃ was added. Subsequently, the mixture was extracted withEt₂O. The organic layer was dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified by column chromatography(Et₂O:hexanes 1:1) to afford4-(4-benzyl-morpholin-2-yl)-N-(2,6-dichloro-phenyl)-benzamide (0.68 g).

4-Benzyl-2-{4-[2-(2,6-dichloro-phenyl)-vinyl]-phenyl}-morpholine: To asuspension of (2,6-dichloro-benzyl)-triphenyl-phosphonium bromide (2.06g; 4.1 mmol) (See: A. Schmidpeter, H. Noeth, G. Jochem, H.-P. Schroedel,K. Karaghiosoff; Chem. Ber., 1995, 128, 379) in THF (25 mL) was addedsodium hydride (60% dispersion in mineral oil) (215 mg; 4.5 mmol), at 0°C. After stirring for 1 hour, 4-(4-benzyl-morpholin-2-yl)-benzaldehyde(1.05 g; 3.7 mmol) was added, at 0° C. Subsequently, the resultingmixture was heated under reflux for 1 hour. After cooling to RT, 5%aqueous NaHCO₃ was added and the mixture extracted with Et₂O. Theorganic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo.The residue was purified by column chromatography (SiO₂, Et₂O:hexanes1:1) to afford4-benzyl-2-{4-[2-(2,6-dichloro-phenyl)-vinyl]-phenyl}-morpholine (1.15g).

4-Benzyl-2-[4-(2,6-dichloro-benzyl)-phenyl]-morpholine

To a mixture of 2,6-dichlorobenzylzinc chloride (7.95 mL; 0.50 mol/l inTHF; 3.97 mmol) and tetrakis(triphenylphosphine)palladium(0) (83.48 mg;0.07 mmol) in THF (25 mL) was added4-benzyl-6-(4-bromo-phenyl)-morpholine (1.20 g; 3.61 mmol). Theresulting mixture was stirred at RT for 2 hours, and subsequently heatedunder reflux, for 2 h. After cooling to RT the mixture was concentratedin vacuo. The residue was partitioned between 5% aqueous NaHCO₃ andEtOAc. The organic layer was dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified by column chromatography (SiO₂,Et₂O:hexanes 1:1) to afford4-benzyl-2-[4-(2,6-dichloro-benzyl)-phenyl]-morpholine (1.40 g).

2-[4-(4-Benzyl-morpholin-2-yl)-phenyl]-1-phenyl-ethanone: To a degassedsolution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (205 mg; 0.62 mmol)and acetophenone (87 μL; 0.74 mmol) in toluene (4 mL) was added NaOtBu(148.3 mg; 1.54 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (38.4mg; 0.06 mmol) and tris(dibenzylideneacetone)dipalladium(0) (28.3 mg;0.03 mmol). The resulting mixture was heated to 110° C. for 30 min. in amicrowave. After cooling to room temperature 5% aqueous NaHCO₃ was addedand the mixture extracted with EtOAc. The combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford2-[4-(4-Benzyl-morpholin-2-yl)-phenyl]-1-phenyl-ethanone (110.00 mg).

Benzhydrylidene-[4-(4-benzyl-morpholin-2-yl)-phenyl]amine

To a degassed solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (4.00g; 12.04 mmol) in toluene (50 mL) was added benzophenone imine (2.42 mL;14.45 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.60 g; 0.96mmol), tris-(dibenzylideneacetone)-dipalladium(0) (0.22 g; 0.24 mmol)and NaOtBu (1.62 g; 16.86 mmol). The resulting mixture was heated to100° C. for 16 hours. After cooling to RT a 5% aqueous NaHCO₃ solutionwas added, and the product was extracted with EtOAc. The combinedorganic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo.The residue was purified by column chromatography (SiO₂, Et₂O:hexanes1:1) to affordbenzhydrylidene-[4-(4-benzyl-morpholin-2-yl)-phenyl]-amine (3.30 g).

4-(4-Benzyl-morpholin-2-yl)-phenylamine

To a solution ofbenzhydrylidene-[4-(4-benzyl-morpholin-2-yl)-phenyl]-amine (3.30 g; 7.63mmol) in THF (50 mL) was added hydrochloric acid (30.5 mL; 1.00 mol/L inwater; 30.5 mmol). The resulting mixture was stirred overnight at RT.The reaction mixture was partitioned between 1M aqueous HCl and EtOAc.The aqueous layer was made basic with 1M aqueous NaOH (pH >10) andextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 4-(4-benzyl-morpholin-2-yl)-phenylamine(1.85 g).

[4-(4-Benzyl-morpholin-2-yl)-phenyl]-(2,6-dichloro-benzyl)-amine

A mixture of 4-(4-benzyl-morpholin-2-yl)-phenylamine (0.82 g; 3.06mmol), DIPEA (1.57 mL; 9.17 mmol) and 2,6-dichlorobenzyl bromide (0.88g; 3.67 mmol) in MeOH (25 mL). was stirred at RT, overnight. Theresulting mixture was partitioned between 5% aqueous NaHCO₃ and EtOAc.The organic layer was dried (Na₂SO₄), filtered and concentrated in vacuoto afford[4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dichloro-benzyl)-amine (1.25g).

N-[4-(4-Benzyl-morpholin-2-yl)-phenyl]-2,6-dichloro-benzamide

To a mixture of 4-(4-benzyl-morpholin-2-yl)-phenylamine (0.48 g; 1.8mmol), and N-ethyldiisopropylamine (0.92 mL; 5.4 mmol) in CH₃CN (10 mL)was added 2,6-dichlorobenzoyl chloride (0.31 mL; 2.2 mmol), at 0° C. Theresulting mixture was allowed to warm to RT, stirred for 1 h, andpartitioned between Et₂O and 5% aqueous NaHCO₃. The organic layer wasdried (Na₂SO₄), filtered, and concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, Et₂O) to affordN-[4-(4-benzyl-morpholin-2-yl)-phenyl]-2,6-dichloro-benzamide (0.61 g).

4-Benzyl-2-{4-[2-(2,6-dichloro-phenyl)-ethyl]-phenyl}-morpholine

To a degassed solution ofpotassium[2-(2,6-dichlorophenyl)ethyl]trifluoroborate (0.28 g; 1 mmol)and potassium phosphate tribasic (0.58 g; 2.7 mmol) in toluene (20 mL)and water (4 mL) was added 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.30g; 0.90 mmol), palladium(II) acetate (6.1 mg; 0.03 mmol), and2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (25.3 mg; 0.05mmol). The resulting mixture was heated under reflux, overnight. Aftercooling to RT, the mixture was concentrated in vacuo and partitionedbetween EtOAc and 5% aqueous NaHCO₃. The organic layer was dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, Et₂O:hexanes 1:1) to afford4-benzyl-2-{4-[2-(2,6-dichloro-phenyl)-ethyl]-phenyl}-morpholine (0.21g).

The required potassium[2-(2,6-dichlorophenyl)ethyl]trifluoroborate wasprepared as follows: To a solution of 2,6-dichlorostyrene (1.58 mL; 11.6mmol) in THF (15 mL) was added chloro(1,5-cyclooctadiene)Iridium(I)dimer (38.8 mg; 0.06 mmol), 1,2-bis(diphenylphosphino)ethane (46.1 mg;0.12 mmol) and pinacolborane (11.6 mL; 1M in THF; 11.6 mmol). Theresulting mixture was stirred at RT, overnight, subsequently,concentrated in vacuo and purified by column chromatography (SiO2,Et₂O:hexanes 1:3). The obtained product was treated with MeOH (56 mL),water (14 mL), and potassium bifluoride (3.43 g; 43.9 mmol), and stirredat RT, overnight. Subsequently, the solvents were removed in vacuo andthe residue treated with toluene and concentrated in vacuo. The lattersteps were repeated three times to remove all the water. The obtainedsolid was treated with CH₃CN, and heated at 50° C. The precipitate wasremoved by filtration and washed with CH₃CN. The combined CH₃CN layerswere concentrated in vacuo and the residue was treated with Et₂O. Theformed precipitate was collected by filtration and dried in vacuo toafford potassium[2-(2,6-dichlorophenyl)ethyl]trifluoroborate (1.12 g),which was used as such.

3-[2-(4-Benzyloxy-phenyl)-5-oxo-morpholin-4-yl]-propionic acidtert-butyl ester

To a mixture of 6-(4-benzyloxy-phenyl)-morpholin-3-one (13.40 g; 47.3mmol) and powdered NaOH (3.78 g; 94.6 mmol) in THF (250 mL) was addedtert-butyl acrylate (13.7 mL; 94.6 mmol). The resulting mixture wasstirred at RT for 2 hours and subsequently concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, Et₂O) to afford3-[2-(4-benzyloxy-phenyl)-5-oxo-morpholin-4-yl]-propionic acidtert-butyl ester (14.20 g).

2-(4-octyloxy-phenyl)-morpholine

To a solution of 4-benzyl-2-(4-octyloxy-phenyl)-morpholine (20.22 g; 53mmol) in MeOH (400 mL) was added palladium hydroxide (0.74 g; 5.30mmol). The mixture was treated with H₂, at normal pressure, overnight.The reaction mixture was filtered over Kieselguhr. The filter-cake waswashed with a solution of ammonia in MeOH. Evaporation of the solventafforded 2-(4-octyloxy-phenyl)-morpholine (14.80 g), which was used assuch in the next step.

The following compounds were obtained according to a similar manner:

-   3-Methyl-4-morpholin-2-yl-phenol-   4-Morpholin-2-yl-phenol-   2-(4-Octyl-phenyl)-morpholine-   2-(4-Hexyloxy-phenyl)-morpholine-   2-(4-Heptyloxy-phenyl)-morpholine-   4-Morpholin-2-yl-2-trifluoromethyl-phenol-   4-(2-Methyl-morpholin-2-yl)-phenol-   2-Methyl-4-morpholin-2-yl-phenol-   2-Methoxy-4-morpholin-2-yl-phenol-   4-(5,5-Dimethyl-morpholin-2-yl)-phenol-   4-Morpholin-2-yl-3-trifluoromethyl-phenol-   3-Fluoro-4-morpholin-2-yl-phenol-   3-[2-(4-Hydroxy-phenyl)-5-oxo-morpholin-4-yl]-propionic acid    tert-butyl ester:-   4-(6,6-Dimethyl-morpholin-2-yl)-phenol-   3-Morpholin-2-yl-phenol-   6-Morpholin-2-yl-pyridin-3-ol

2-(4-Phenethyl-phenyl)-morpholine

A mixture of4-benzyl-2-{4-[2-(2,6-dichloro-phenyl)-vinyl]-phenyl}-morpholine (0.54g; 1.27 mmol) and palladium hydroxide (0.04 g; 0.25 mmol) in MeOH (25mL) was treated with H₂, at normal pressure, overnight. The resultingmixture was filtered over Kieselguhr and the solvents evaporated toafford 2-(4-phenethyl-phenyl)-morpholine (0.34 g).

(+)-2-(4-octyloxy-phenyl)-morpholine and(−)-2-(4-octyloxy-phenyl)-morpholine

Racemic 2-(4-octyloxy-phenyl)-morpholine was separated into both opticalisomers by preparative chiral HPLC, at RT on a CHIRALPAK® IA 20μm−250×76 mm column, with as mobile phase 99.9% CH₃CN/0.1% diethylamine(v/v) at a flow rate of 270 mL/min., and with UV-detection at 240 nm.This afforded after evaporation of the solvents(+)-2-(4-octyloxy-phenyl)-morpholine (e.e. 98.3%; [α]_(D) ²⁵=+24 (c 1.0,MeOH)) and (−)-2-(4-octyloxy-phenyl)-morpholine (e.e. 99.0%, [α]_(D)²⁵=−28 (c 1.0, MeOH)).

2-[4-(2,6-Dichloro-phenoxymethyl)-phenyl]-morpholine

To a solution of4-benzyl-2-[4-(2,6-dichloro-phenoxymethyl)-phenyl]-morpholine (2.25 g;3.7 mmol) in 1,2-dichloroethane (10 mL), was added dropwise1-chloroethyl chloroformate (0.44 mL; 4.0 mmol), at 0° C. After 15minutes, the cooling was removed and subsequently the mixture was heatedunder reflux overnight. After cooling to RT the mixture was concentratedin vacuo. To the residue was added toluene and the mixture wasconcentrated in vacuo. This last step was repeated twice. To the finalresidue was added MeOH (10 mL), and this mixture was stirred overnightat RT. Once more the mixture was concentrated in vacuo. The residue waspartitioned between EtOAc and 2 M Aqueous NaOH. The layers wereseparated, and the organic layer dried (Na₂SO₄), filtered, andconcentrated in vacuo to afford2-[4-(2,6-Dichloro-phenoxymethyl)-phenyl]-morpholine (0.98 g), which wasused as such in the next step.

The following compounds were obtained according to a similar manner:

-   N-(2,6-Dichloro-phenyl)-4-morpholin-2-yl-benzamide-   2-{4-[2-(2,6-Dichloro-phenyl)-vinyl]-phenyl}-morpholine-   (2,6-Dichloro-benzyl)-(4-morpholin-2-yl-phenyl)-amine-   2,6-Dichloro-N-(4-morpholin-2-yl-phenyl)-benzamide-   2-{4-[2-(2,6-Dichloro-phenyl)-ethyl]-phenyl}-morpholine-   2-[4-(2,6-dichloro-benzyl)-phenyl]-morpholine-   2-[3-Chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-   2-[3-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholine-   2-[3-Chloro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholine-   2-[2-Chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-   2-(4-Morpholin-2-yl-phenyl)-1-phenyl-ethanone

2-(4-Hydroxy-phenyl)-morpholine-4-carboxylic acid tert-butyl ester

A mixture of 4-morpholin-2-yl-phenol (0.99 g; 5.41 mmol) anddi-tert-butyl dicarbonate (1.18 g; 5.41 mmol) in CH₃CN (50 mL) wasstirred at RT for 3 days. Subsequently, the resulting mixture wasconcentrated in vacuo and the residue was purified by columnchromatography (SiO₂, CH₂Cl₂:CH₃OH 97:3) to afford2-(4-hydroxy-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.15g).

The following compound was obtained according to a similar manner:

-   2-(4-Bromo-phenyl)-thiomorpholine-4-carboxylic acid tert-butyl ester

2-(4-Bromo-phenyl)-1,1-dioxo-1λ⁶-thiomorpholine-4-carboxylic acidtert-butyl ester

To a solution of 2-(4-bromo-phenyl)-thiomorpholine-4-carboxylic acidtert-butyl ester (3.60 g; 10.05 mmol) in CH₂Cl₂ (100 mL) was added3-chloroperoxybenzoic acid (5.20 g; 30.14 mmol), at 0° C. The resultingmixture was stirred overnight at RT, and subsequently, a saturatedaqueous sodium thiosulfate solution was added and the mixture stirredfor another 30 min. The layers were separated and the aqueous layer wasextracted twice with EtOAc. The combined EtOAc layers were washed twicewith an aqueous Na₂CO₃ solution. The combined organic layers were dried(MgSO₄), filtered and concentrated in vacuo to afford2-(4-bromo-phenyl)-1,1-dioxo-1λ⁶-thiomorpholine-4-carboxylic acidtert-butyl ester (4.06 g) which was used as such in the next step.

2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholine hydrochloride

Acetyl chloride (1.35 mL, 8.9 mmol) was added to ethanol (60 mL). Theresulting solution was added to2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine-4-carboxylic acidtert-butyl ester (1.54 g; 3.4 mmol), at RT. The resulting mixture wasstirred at 60° C. for 3 hours, and subsequently, at RT for three days.The resulting suspension was concentrated in vacuo, and treated withiPr₂O. The formed precipitate was collected by filtration and dried invacuo to afford 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholinehydrochloride (1.31 g).

The following compound was obtained according to a similar manner:

-   2-(4-Bromo-phenyl)-thiomorpholine 1,1-dioxide

3-[2-(4-Hydroxy-2-methyl-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester

A mixture of 3-methyl-4-morpholin-2-yl-phenol (14.26 g; 73.8 mmol) andtert-butyl acrylate (21.4 ml; 147.6 mmol) in CH₃CN (250 mL) was heatedunder reflux overnight. After cooling to RT the mixture was concentratedin vacuo, and the residue was partitioned between EtOAc and 5% aqueousNaHCO₃ solution. The organic layer was dried (Na₂SO₄), filtered,concentrated in vacuo, and purified by column chromatography (SiO₂,CH₂Cl₂>Et₂O/hexanes 1:1>Ether) to afford3-[2-(4-hydroxy-2-methyl-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester (22.62 g).

The following compounds were obtained according to a similar manner:

-   3-[2-(4-Hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl    ester-   Isomer 1 of 3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester from (+)-2-(4-octyloxy-phenyl)-morpholine.-   Isomer 2 of 3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester from (−)-2-(4-octyloxy-phenyl)-morpholine.-   3-[2-(4-Octyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl    ester.-   3-[2-(4-Hexyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl    ester-   3-[2-(4-Heptyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl    ester-   3-[2-(4-Hydroxy-3-trifluoromethyl-phenyl)-morpholin-4-yl]-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-phenylcarbamoyl)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-phenoxymethyl)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-(2-{4-[2-(2,6-Dichloro-phenyl)-vinyl]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-[2-(4-Phenethyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl    ester-   3-{2-[4-(2,6-Dichloro-benzylamino)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzoylamino)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(4-Hydroxy-phenyl)-2-methyl-morpholin-4-yl]-propionic acid    tert-butyl ester.-   3-(2-{4-[2-(2,6-Dichloro-phenyl)-ethyl]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester.-   3-[2-(4-Hydroxy-3-methyl-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester.-   3-[2-(4-Hydroxy-3-methoxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester.-   3-{2-[4-(2,6-Dichloro-benzyl)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester.-   3-[2-(4-Hydroxy-phenyl)-5,5-dimethyl-morpholin-4-yl]-propionic acid    tert-butyl ester.-   3-[2-(4-Hydroxy-2-trifluoromethyl-phenyl)-morpholin-4-yl]-propionic    acid tert-butyl ester-   3-[2-(2-Fluoro-4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-[6-(4-Hydroxy-phenyl)-2,2-dimethyl-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-{2-[3-Chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[3-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[3-Chloro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(3-Hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl    ester-   3-{2-[2-Chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(4-Bromo-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl    ester-   3-[2-(4-Bromo-phenyl)-1,1-dioxo-1λ⁶-thiomorpholin-4-yl]-propionic    acid tert-butyl ester-   3-[2-(5-Hydroxy-pyridin-2-yl)-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-{2-[4-(2-Oxo-2-phenyl-ethyl)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionitrile    using acrylonitrile instead of tert-butyl acrylate.

3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtert-butyl ester

A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester (5.00 g; 16.3 mmol) and K₂CO₃ (6.74 g; 48.8 mmol) inCH₃CN (100 mL) was stirred for one hour at RT. Subsequently2,6-dichlorobenzyl bromide (4.29 g; 17.9 mmol) was added and theresulting mixture was stirred overnight at RT. The reaction mixture waspartitioned between EtOAc (250 mL) and 5% aqueous NaHCO₃ solution (100mL). The layers were separated and the organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO2, Et₂O/hexanes 1:1) to afford3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtert-butyl ester (7.40 g).

The following compounds were obtained according to a similar manner:

-   3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acid tert-butyl    ester-   3-{2-[4-(2-Chloro-6-fluorobenzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Difluoro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-3-trifluoromethyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-2-methyl-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-2-methyl-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Trifluoromethyl-benzyloxy)-phenyl]-2-methyl-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-Methyl-2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester-   2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholine-4-carboxylic acid    tert-butyl ester-   3-{2-[3-Methoxy-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-3-methoxy-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-3-methoxy-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[3-Methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-3-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-3-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl    ester3-{2-[4-(2-Chloro-5-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Phenyl-allyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-5-oxo-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(4-Octyloxy-phenyl)-5-oxo-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-5,5-dimethyl-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[5,5-Dimethyl-2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-{6-[4-(2,6-Dichloro-benzyloxy)-phenyl]-2,2-dimethyl-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2,2-Dimethyl-6-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-2-fluoro-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Fluoro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-2-fluoro-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(4-Octyloxy-2-trifluoromethyl-phenyl)-morpholin-4-yl]-propionic    acid tert-butyl ester

3-{2-[4-(2,6-Dichloro-3-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required 2-bromomethyl-1,3-dichloro-4-ethyl-benzene was prepared asfollows: To a mixture of 2′,4′-dichloroacetophenone (4.85 g; 25.66 mmol)suspended in diethylene glycol (20 mL) was added KOH (2.37 g; 35.92mmol) and hydrazine hydrate (2.9 mL). The resulting mixture was heatedat 100° C. (for 1 hour) and subsequently overnight, at 200° C. Aftercooling to RT, the mixture was partitioned between Et₂O and water. Thelayers were separated and the organic layer was dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, hexanes) to afford the product:2,4-dichloro-1-ethylbenzene (2.24 g). To a solution2,2,6,6-tetramethylpiperidine (2.36 mL; 14 mmol), dissolved in THF (40ml) was added a solution of n-BuLi in hexanes (5.6 mL; 2.50 mol/l; 14mmol), at −78° C. The reaction mixture was stirred for 90 minutes,allowing the temperature to reach 0° C. Subsequently, a solution of2,4-dichloro-1-ethylbenzene (2.23 g; 12.74 mmol), dissolved in THF (5mL) was added at −78° C. The resulting mixture was stirred for 2.5hours. Subsequently, DMF (1.48 mL; 19.11 mmol) was added dropwise andthe resulting mixture was stirred for 30 minutes. The reaction wasquenched by the addition of a saturated aqueous NH₄Cl solution, at −50°C. The resulting mixture was extracted with Et₂O. The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated in vacuo toafford the crude 2,6-dichloro-3-ethylbenzaldehyde, which was redissolvedin MeOH (100 mL). Subsequently, NaBH₄ (1.45 g; 38.22 mmol) was added, insmall portions, at 0° C. After the addition was complete the mixture wasallowed to warm to RT and stirred for one hour. Subsequently, themixture was cooled to 0° C., water was added, and the MeOH evaporated invacuo. To the aqueous solution was added a 5% aqueous NaHCO₃ solutionand Et₂O. The layers were separated and the organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, Et₂O:hexanes 1:7 followed by 1:1) toafford (2,6-dichloro-3-ethylphenyl)methanol (2.11 g). To a solution of(2,6-dichloro-3-ethylphenyl)methanol (0.79 g; 3.85 mmol) in Et₂O (25 mL)was added dropwise PBr₃ (0.47 ml; 5.01 mmol), at 0° C., and theresulting mixture was stirred overnight, at RT. Subsequently, water wasadded, at 0° C., followed by EtOAc en 5% aqueous NaHCO₃. The layers wereseparated and the organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo to afford2-bromomethyl-1,3-dichloro-4-ethyl-benzene (0.57 g), which was used assuch.

(+)-3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester and(−)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

Racemic3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtert-butyl ester (7.1 gram) was separated into both optical isomers bypreparative chiral HPLC, at 24° C. on a CHIRALPAK® T304 20 μm-270×110 mmcolumn, with as mobile phase 60% n-heptane/40% isopropanol (v/v) at aflow rate of 570 mL/min., and with UV-detection at 225 nm. This affordedafter evaporation of the solvents(+)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester (3.38 g; e.e. >99.5%, [α]_(D) ²⁵=+13 (c 1.0,MeOH)). and(−)-3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester (3.38 g; e.e. 99.0%, [α]_(D) ²⁵=−12 (c 1.0,MeOH)).

3-{2-[4-(2,6-Dimethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtert-butyl ester

To a solution of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester (0.45 g; 1.5 mmol) in THF (10 mL) was added2,6-dimethylbenzyl alcohol (0.22 g; 1.6 mmol), followed by DIAD (0.43mL; 2.2 mmol) and triphenylphosphine (0.58 g; 2.2 mmol). The resultingmixture was stirred at RT for 3 days. Subsequently, the reaction mixturewas concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Et₂O:hexanes 2:1) to afford3-{2-[4-(2,6-dimethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtert-butyl ester (0.38 g).

The following compounds were obtained according to a similar manner:

-   3-{2-[4-(3,5-Dichloro-pyridin-4-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-(2-{4-[1-(2,6-Dichloro-phenyl)-ethoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester.-   3-{2-[4-(2,3-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester.-   3-{2-[4-(2,3,6-Trichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester.-   3-{2-[4-(2-Chloro-6-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester.

3-{2-[4-(2,4-Dichloro-pyridin-3-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2,4-dichloro-pyridin-3-yl)-methanol was prepared asfollows: To a solution of 2,4-dichloropyridine (3.00 mL; 27.8 mmol) inTHF (25 mL) was added dropwise a solution of LDA (15.3 mL; 2.00 mol/l inTHF/heptane/ethylbenzene; 30.6 mmol), at −78° C. The resulting mixturewas stirred at −78° C. for 1 h. Subsequently, a solution of ethylchloroformate (3.2 mL; 33.33 mmol) in THF (5 mL), was added dropwise, at−78° C. and the mixture was stirred for another 1 h at the sametemperature. To the resulting mixture was added 5% aqueousNaHCO₃-solution, dropwise, at −78° C. The mixture was allowed to warm toRT and extracted with EtOAc. The organic layer was dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, Et₂O:hexanes 1:3) to afford 2,4-dichloro-nicotinic acid ethylester (2.45 g). To a solution of 2,4-dichloro-nicotinic acid ethyl ester(2.35 g; 10.68 mmol) in THF (50 mL) was added dropwisediisobutylaluminum hydride (32.0 mL; 1.00 mol/l in THF, 32.0 mmol), at4° C. After 15 minutes the ice-bath was removed and the reaction mixturewas stirred at RT overnight. Subsequently, the resulting mixture wasconcentrated in vacuo and partitioned between 5% aqueous NaHCO₃ andEtOAc. The layers were separated and the organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by columnchromatography (Et₂O:hexanes 1:1) to afford(2,4-dichloro-pyridin-3-yl)-methanol (0.40 g).

3-{2-[4-(2-Chloro-5-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-5-methylphenyl)methanol was prepared as follows:To a solution of 2-chloro-5-methylbenzoic acid (2.05 g; 12.2 mmol) inTHF (20 mL) was added BH₃.THF complex in THF (1 mol/1, 24.0 mL; 24.0mmol) dropwise and subsequently stirred for 2 hours at 60° C. To thereaction mixture was added 1 M aqueous HCl (30 mL), at 0° C., and theresulting mixture was stirred at RT for 10 minutes. The resultingmixture was concentrated in vacuo and the residue was partitionedbetween EtOAc and 5% aqueous NaHCO₃-solution. The organic layer wasdried (Na₂SO₄), filtered, and concentrated in vacuo to afford theproduct (1.8 g), which was used as such in the next step.

3-{2-[4-(2-Chloro-5-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-5-ethylphenyl)methanol was prepared as follows:To a nitrogen purged solution of ethyl 5-bromo-2-chlorobenzoate (4.3 mL,25.1 mmol) in THF (100 mL) was added lithium chloride (2.12 g, 50.1mmol) and Pd(dppf)Cl₂ (0.82 g, 1 mmol). Subsequently, the mixture wascooled to −78° C., and a solution of diethylzinc in heptane (37.6 mL;1.00 mol/1; 37.6 mmol) was added dropwise. The reaction mixture wasallowed to come to RT overnight. The resulting reaction mixture wascooled to −10° C. and diluted with Et₂O (300 mL). Subsequently, a 1 Maqueous HCl solution (150 mL) was added carefully. The layers wereseparated, and the organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, Et₂O:hexanes 5:95) to afford ethyl 2-chloro-5-ethylbenzoate (4.61g). To a nitrogen purged solution of ethyl 2-chloro-5-ethyl-benzoate (1g, 4.70 mmol) in THF (25 mL), was added diisobutylaluminiumhydride(14.11 mL; 14.11 mmol) in toluene, at −5° C. The reaction mixture wasallowed to come to RT and stirred overnight. The resulting reactionmixture was cooled to −10° C. and a 5% aqueous NaHCO₃-solution (10 mL)was added. The layers were separated, and the organic layer was dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, Et₂O:hexanes 1:3 followed byEt₂O:hexanes 1:1) to afford (2-chloro-6-ethylphenyl)methanol (0.59 g)which was used as such.

3-{2-[4-(2-Chloro-5-propyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-5-propylphenyl)methanol was prepared in a similarway as described for (2-chloro-5-ethylphenyl)methanol using N-propylzincbromide instead of diethylzinc.

3-{2-[4-(2-Chloro-5-isopropyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-5-isopropylphenyl)methanol was prepared in asimilar way as described for (2-chloro-5-ethylphenyl)methanol usingdiisopropyl zinc instead of diethylzinc.

3-{2-[4-(2,4,6-Trichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester3-{2-[4-(2,6-Dichloro-4-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required [2,6-dichloro-4-(trifluoromethyl)-phenyl]nethanol wasprepared as follows: To a solution of1,3-dichloro-5-(trifluoromethyl)benzene (4.73 g; 22 mmol) in THF (40 mL)was added n-BuLi in hexanes (8 mL; 2.50 mol/1; 20 mmol), at −78° C. Theresulting mixture was stirred for 15 minutes and poured onto dry ice inTHF. The reaction mixture was acified to pH=3 (with 5 M aqueous HClsolution) and extracted with EtOAc. The organic layer was dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, CH₂Cl₂/MeOH 8:2) to afford2,6-dichloro-4-(trifluoromethyl)benzoic acid (1.2 g). To a solution ofthis 2,6-dichloro-4-(trifluoromethyl)benzoic acid (1.7 g; 6.6 mmol) inTHF (20 mL) was added dropwise a solution of borane-THF complex in THF(1 mol/1, 13.3 mL; 13.3 mmol). Subsequently, the resulting mixture wasstirred overnight at 60° C. To the reaction mixture was added 1 Maqueous HCl (30 mL), at 0° C., and the resulting mixture was stirred atRT for 10 minutes. The resulting mixture was concentrated in vacuo andthe residue was partitioned between EtOAc and 5% aqueousNaHCO₃-solution. The layers were separated and the organic layer wasdried (Na₂SO₄), filtered, and concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, Et₂O:hexanes 1:3 followed byEt₂O:hexanes 1:1) to afford[2,6-dichloro-4-(trifluoromethyl)phenyl]-methanol (1.3 g), which wasused as such in the next step.

3-{2-[4-(2,6-Dichloro-4-iodo-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2,6-dichloro-4-iodophenyl)methanol was prepared asfollows: To a solution of 3,5-dichloroiodobenzene (2.72 g; 10 mmol) inTHF (25 mL) was added a lithium diisopropylamide solution inTHF/heptane/ethylbenzene (5.5 mL; 2.00 mol/1; 11 mmol), at −78° C. Theresulting mixture was stirred for 4.5 hour, at −78° C., and subsequentlya solution of DMF (1.2 mL, 15 mmol) in THF (5 mL) was added dropwise, at−78° C. The resulting reaction mixture was stirred for 2 hours at −40°C. Subsequently, the reaction was quenched by the addition of an 5%aqueous NH₄CI solution, at −20° C. The resulting mixture was extractedwith Et₂O. The combined organic layers were dried (Na₂SO₄), filtered,and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Et₂O:hexanes 1:3) to afford the2,6-dichloro-4-benzaldehyde (0.7 g, 23%). To a solution of2,6-dichloro-4-benzaldehyde (450 mg, 1.3 mmol) in MeOH (15 mL) was addedNaBH₄ (72.14 mg; 1.9 mmol), in small portions, at 0° C. After theaddition was complete the mixture was allowed to warm to RT and stirredfor one hour. Subsequently, the mixture was cooled to 0° C., water wasadded, and the MeOH evaporated in vacuo. To the aqueous solution wasadded a 5% aqueous NaHCO₃ solution and EtOAc. The layers were separatedand the organic layer was dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by column chromatography (CH₂Cl₂/acetone95:5) to afford (2,6-dichloro-4-iodophenyl)methanol (0.42 g) which wasused as such.

-   3-(2-{4-[3-(2-Fluoro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-(2-{4-[3-(2-Trifluoromethyl-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-(2-{4-[3-(2-Chloro-6-fluoro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-(2-{4-[3-(2,6-Dichloro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-(2-{4-[3-(4-Chloro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-(2-{4-[3-(2-Chloro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-(2-{4-[3-(2,3-Difluoro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-(2-{4-[3-(4-Chloro-phenyl)-allyloxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-{2-[4-(3-Phenyl-prop-2-ynyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-(2-{4-[3-(4-Chloro-phenyl)-prop-2-ynyloxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-{2-[4-(Indan-1-yloxy)-phenyl]-morpholin-4-yl}-propionic acid

3-{2-[4-(7-Methyl-indan-1-yloxy)-phenyl]-morpholin-4-yl}-propionic acid

The required 7-methyl-indan-1-ol was prepared as follows: To a solutionof 7-methyl-1-Indanone (0.94 g; 6.43 mmol) in EtOH (50 mL) was addedNaBH₄ (0.78 g; 20.6 mmol), at 0° C. The resulting mixture stirred at RTovernight, subsequently water (5 mL) was added and the resulting mixturestirred for 10 min. The mixture was concentrated in vacuo, the residuewas dissolved in EtOAc and washed with water and brine, dried (MgSO₄)filtered, and concentrated in vacuo to afford 0.7-methyl-indan-1-ol(0.85 g), which was used as such.

3-{2-[4-(2,3-Dihydro-benzofuran-3-yloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required 2,3-dihydro-benzofuran-3-ol was prepared according to:Ghosh, S. et al Tetrahedron, 1989, 45, 1441-1446.

3-{2-[4-(2,6-Dichloro-4-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

The required (2,6-Dichloro-4-methyl-phenyl)-methanol was prepared asfollows: To 1-bromo-3,5-dichlorobenzene (2.50 g; 11.1 mmol) was added asolution of LiCl in THF (44.3 mL; 0.50 mol/1; 22.2 mmol) and Pd(dppf)Cl₂(0.32 g; 0.44 mmol). The resulting mixture was cooled to −78° C. and asolution of methylzinc chloride in THF (11.1 mL; 2 mol/1; 22.2 mmol) wasadded dropwise, subsequently the mixture was slowly heated to 50° C. for4 hours. After cooling to RT, 1M aqueous HCl and Et₂O were added and thelayers were separated. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, hexanes/CH₂Cl₂ 95:5) to afford 1,3-dichloro-5-methyl-benzene.

To a solution of 1,3-dichloro-5-methyl-benzene (0.95 g; 5.90 mmol) inTHF (20 mL) was added dropwise a solution of n-BuLi in hexane (2.4 mL;2.5 mol/l; 6 mmol) at −78° C. After 15 min at −78° C., the resultingmixture was poured onto dry ice in THF and allowed to come to RTovernight. Subsequently the reaction mixture was acidified with 1Maqueous HCl and extracted with CH₂Cl₂. The combined organic layers weredried (MgSO₄), filtered and concentrated in vacuo to afford2,6-dichloro-4-methyl-benzoic acid (1.35 g), which was used as such.

To a solution of 2,6-dichloro-4-methyl-benzoic acid (1.35 g; 6.58 mmol)in THF (13.5 mL) was added dropwise a solution of BH₃.THF in THF (19.8mL; 1.00 mol/1; 19.8 mmol), at 0° C. After complete addition theresulting mixture was heated under reflux, overnight. Subsequently, themixture was cooled to 0° C. and 1M aqueous HCl (40 mL) was addedfollowed after 10 min. by Et₂O (100 mL). The layers were separated; theaqueous layer extracted with Et₂O, and the combined organic layers werewashed with brine, dried (MgSO₄), filtered, and concentrated in vacuo.The residue was purified by column chromatography (SiO₂, Et₂O/hexanes1:2) to afford 2,6-dichloro-4-methyl-phenyl)-methanol (0.80 g).

3-{2-[4-(2-Chloro-6-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-6-ethyl-phenyl)-methanol was prepared as follows:To a solution of 2-chloro-6-ethylbenzaldehyde (1.8 g, 10.67 mmol),prepared according to US2007/197621, (see also W02007/85556 and U.S.Pat. No. 6,380,387) in MeOH (50 mL) was added NaBH₄ (1.21 g; 32.02mmol), in small portions, at 0° C. After the addition was complete themixture was allowed to warm to RT and stirred for one hour.Subsequently, the mixture was cooled to 0° C., water was added, and theMeOH evaporated in vacuo. To the aqueous solution was added a 5% aqueousNaHCO₃ solution and EtOAc. The layers were separated and the organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, Et₂O:hexanes 1:7followed by Et₂O:hexanes 3:1) to afford (2-chloro-6-ethylphenyl)methanol(1.2 g).

3-{2-[4-(2-Chloro-6-isopropyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-6-isopropyl-phenyl)-methanol was obtained from aNaBH₄ reduction of 2-chloro-6-isopropyl-benzaldehyde in MeOH, which wasprepared in a similar manner as 2-chloro-6-ethylbenzaldehyde.

3-{2-[4-(2-Chloro-6-cyclopropyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-6-cyclopropyl-phenyl)-methanol was obtained froma NaBH₄ reduction of 2-chloro-6-cycloopropyl-benzaldehyde in MeOH, whichwas prepared in a similar manner as 2-chloro-6-ethylbenzaldehyde.

3-{2-[4-(2-Chloro-6-isobutyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-6-isobutyl-phenyl)-methanol was obtained from aNaBH₄ reduction of 2-chloro-6-isobutyl-benzaldehyde in MeOH, which wasprepared in a similar manner as 2-chloro-6-ethylbenzaldehyde.

-   3-[2-(3-Benzyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl    ester-   3-[2-(3-Octyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl    ester-   3-{2-[3-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[3-(2-Chloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester

3-{2-[4-(2,6-Dichloro-4-prop-1-ynyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2,6-dichloro-4-prop-1-ynyl-phenyl)-methanol was preparedas follows: To a degassed solution of(2,6-dichloro-4-iodophenyl)methanol (3.00 g; 9.90 mmol) in Et₃N (80 ml),in a microwave pressure file, was added CuI (0.19 g; 0.99 mmol) andPdCl₂(PPh₃)₂ (0.35 g; 0.50 mmol). The pressure file was flushed withnitrogen-gas and charged with propyne to a pressure of 5 bar.Subsequently, the vessel was heated in a microwave at 50° C. for 15 min.and thereafter at 80° C. for 10 min. After cooling to room temperaturethe pressure was released and the volatiles removed in vacuo. Theresidue was dissolved in CH₂Cl₂ and washed with water. The organic layerwas concentrated in vacuo, and the residue was purified by columnchromatography to afford (2,6-dichloro-4-prop-1-ynyl-phenyl)-methanol(1.79 g).

3-{2-[4-(2,6-Dichloro-4-propyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2,6-dichloro-4-propyl-phenyl)-methanol was prepared asfollows: A mixture of (2,6-dichloro-4-prop-1-ynyl-phenyl)-methanol (800mg; 3.72 mmol) and Raney Nickel (20 mg) in EtOH (15 mL) was treated withhydrogen gas (1 atm.) overnight, at RT. Subsequently, the catalyst wasremoved by filtration and the filtrate was concentrated in vacuo toafford (2,6-dichloro-4-propyl-phenyl)-methanol (790.0 mg).

3-{2-[4-(2,6-Dichloro-4-isopropyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2,6-dichloro-4-isopropyl-phenyl)-methanol was preparedfrom (2,6-dichloro-4-isopropenyl-phenyl)-methanol in a similar way asdescribed for (2,6-dichloro-4-propyl-phenyl)-methanol.(2,6-Dichloro-4-isopropenyl-phenyl)-methanol was prepared as follows: Toa degassed mixture of (2,6-dichloro-4-iodophenyl)methanol (1.50 g; 4.95mmol), Cs₂CO₃ (9.68 g; 29.71 mmol) and2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.85 ml; 9.90mmol) in 1,2-dimethoxyethane (20 mL) and water (5 mL), was addedPd(dppf)Cl₂ (0.36 g; 0.50 mmol). The resulting mixture was stirred at RTfor three days, and subsequently EtOAc and water were added. The layerswere separated and the aqueous layer was extracted twice with EtOAc. Thecombined organic layers were dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by column chromatography (SiO₂,CH₂Cl₂/hexanes 2:1) to afford(2,6-dichloro-4-isopropenyl-phenyl)-methanol (0.96 g)

3-{2-[4-(2-Chloro-6-trifluoromethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-6-trifluoromethoxy-phenyl)-methanol was preparedas follows: To a solution of 2,2,6,6-tetramethylpiperidine (2.35 ml; 14.mmol) in THF (25 mL) was added dropwise a solution of n-BuLi in hexanes(5.60 ml; 2.50 mol/1; 14 mmol), at −78° C. The resulting mixture wasstirred for 60 min. at −78° C., and subsequently a solution of3-(trifluoromethoxy)chlorobenzene (2.50 g; 12.72 mmol) in THF (10 mL),was added dropwise, at −78° C. After 2.5 hours, at −78° C., DMF (1.48mL, 19.11 mmol) was added dropwise, and stirring was continued foranother 30 min. after which time a saturated aqueous NH₄CI solution wasadded followed by the addition of Et₂O. After warming to RT the layerswere separated, and the organic layer was washed with water, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was dissolvedin MeOH (25 mL) and NaBH₄ (1.44 g; 38.16 mmol) was added portion wise.After complete addition the mixture was allowed to warm to RT andstirred for 30 minutes. Subsequently, water (5 mL) was added and thevolatiles were removed in vacuo. Et₂O and 5% aqueous NaHCO₃ solutionwere added, and the organic layer was separated, dried (Na₂SO₄),filtered and concentrated in vacuo to afford(2-chloro-6-trifluoromethoxy-phenyl)-methanol (2.10 g), which was usedas such.

3-{2-[4-(2-Chloro-4-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-4-methyl-phenyl)-methanol was prepared asfollows: To a solution of 2-chloro-4-methylbenzoic acid (2.18 g; 12.8mmol) in THF (22 mL) was added dropwise a solution of BH₃.THF in THF(25.6 ml; 1.00 mol/l; 25.6 mmol), at 0° C. Upon complete addition theresulting mixture was heated under reflux, for 3 hours. Subsequently,the mixture was cooled to 0° C., 1M aqueous HCl (30 mL) was addeddropwise, and the mixture was stirred for 10 min. Et₂O (100 mL) wasadded and the layers were separated. The organic layer was washed with1M aqueous HCl (2×), 5% aqueous NaHCO₃ (2×), and brine, dried (Na₂SO₄),filtered and concentrated in vacuo to afford(2-chloro-4-methyl-phenyl)-methanol (1.80 g), which was used as such.

3-{2-[4-(2-Chloro-3-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-Chloro-3-methyl-phenyl)-methanol was prepared in asimilar manner as described for (2-Chloro-4-methyl-phenyl)-methanol

-   3-{2-[4-(2,4-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester.-   3-{2-[4-(4-Methoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester.-   3-{2-[4-(2-Methoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester.-   3-{2-[4-(4,4-Dimethyl-cyclohexyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester.-   3-{2-[4-(2-Difluoromethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester.

3-{2-[4-(2,6-Diethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtert-butyl ester

The required (2,6-diethyl-phenyl)-methanol was prepared as follows: To amixture of 2,6-difluorobenzaldehyde (25.00 g; 175.93 mmol) and p-TsOH(0.67 g; 3.52 mmol) in toluene (150 mL) was added 1-aminobutane (16.5mL; 167.1 mmol). The resulting mixture was stirred at RT for 24 hours,subsequently, washed with 5% aqueous NaHCO₃ solution, water and brine,dried (Na₂SO₄), filtered and concentrated in vacuo to affordbutyl-(2,6-difluoro-benzylidene)-amine (35.36 g).

To a solution of butyl-(2,6-difluoro-benzylidene)-amine (1.10 g; 5.58mmol) in THF (25 mL) was added dropwise a solution of ethylmagnesiumbromide in Et₂O (4.1 ml; 3.00 mol/l; 12.3 mmol) at −10° C. After theaddition was completed the reaction mixture was stirred at RT for 4hours. The reaction mixture was quenched by dropwise addition of a 5%aqueous NaHCO₃-solution, and then extracted with EtOAc. The combinedorganic layers were dried (Na₂SO₄), filtered, and concentrated in vacuoto afford butyl-(2,6-diethyl-benzylidene)-amine (1.10 g).

To a solution of butyl-(2,6-diethyl-benzylidene)-amine (1.10 g; 5.06mmol) in water (20 mL) was added H₂SO₄ (5.00 ml; 93.80 mmol), and theresulting mixture was heated under reflux for 2 hours. After cooling toRT the mixture was diluted with EtOAc, and washed with water, a 5%aqueous NaHCO₃-solution and brine. The organic phase was dried (Na₂SO₄),filtered and concentrated in vacuo to afford 2,6-diethyl-benzaldehyde(0.72 g).

To a solution of 2,6-diethyl-benzaldehyde (0.68 g; 4.19 mmol) in THF (15mL) was added dropwise a solution of BH₃.THF in THF (8.38 ml; 1.00mol/l; 8.38 mmol), at 0° C. After complete addition the mixture washeated under reflux for 3 hours. Subsequently, the resulting mixture wascooled to 0° C. and 1M aqueous HCl (10 ml) was added dropwise. Themixture was allowed to warm to room temperature (˜10 min.), and treatedwith Et₂O. The layers were separated, the organic layer washed with 1Maqueous HCl (2×), 5% aqueous NaHCO₃ (2×), and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to afford(2,6-diethyl-phenyl)-methanol (0.67 g), which was used as such.

-   3-{2-[4-(3-Trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-ethyl-benzyloxy)-2-trifluoromethyl-phenyl]morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-trifluoromethoxy-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-isopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-cyclopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[5-(2,6-Dichloro-benzyloxy)-pyridin-2-yl]-morpholin-4-yl}-propionic    acid tert-butyl ester

3-{2-[4-(2-Chloro-6-difluoromethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

The required (2-chloro-6-difluoromethoxy-phenyl)-methanol was preparedas follows: To a solution of 2-chloro-6-hydroxy-benzaldehyde (1.00 g;6.39 mmol) and KOH (7.17 g; 127.7 mmol) in CH₃CN (20 mL) and water (20mL) was added bromodifluoromethyl diethylphosphonate (1.25 ml; 7.03mmol), at −15° C. After 30 minutes the mixture was allowed to warm toRT, stirred for another 30 min. and then treated with 1M aqueous HCl andextracted with Et₂O. The combined organic layers were dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Et₂O/hexanes 1:3), to afford2-chloro-6-difluoromethoxy-benzaldehyde (0.68 g).

To a solution of 2-chloro-6-difluoromethoxy-benzaldehyde (0.65 g; 3.15mmol) in MeOH (10 mL) was added NaBH₄ (357.13 mg; 9.44 mmol), at −15° C.After complete addition the mixture was allowed to warm to RT andstirred for 30 minutes. Subsequently, water (5 mL) was added and thevolatiles were removed in vacuo. The residue was partitioned betweenEt₂O and 5% aqueous NaHCO₃. The layers were separated and the organiclayer was dried (Na₂SO₄), filtered, and concentrated in vacuo to afford(2-chloro-6-difluoromethoxy-phenyl)-methanol (0.52 g), which was used assuch.

3-{2-[4-(2-Chloro-6-difluoromethoxy-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

2,6-Dichloro-benzoic acid4-[4-(2-tert-butoxycarbonyl-ethyl)-morpholin-2-yl]-phenyl ester

To a solution of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester (0.39 g; 1.27 mmol) and N-ethyldiisopropylamine (0.65mL, 3.81 mmol) in CH₃CN (5 mL) was added 2,6-dichlorobenzoyl chloride(0.44 ml; 3.0 mmol), at 0° C. Subsequently, the mixture was allowed towarm to RT and was stirred for 2 days at roomtemperature. The resultingmixture was partitioned between Et₂O and 5% aqueous NaHCO₃ solution. Thelayers were separated and the organic layer was dried (Na₂SO₄), filteredand concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Et₂O to afford 2,6-dichloro-benzoic acid4-[4-(2-tert-butoxycarbonyl-ethyl)-morpholin-2-yl]-phenyl ester (0.51g).

4-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester

2-(4-Octyloxy-phenyl)-morpholine (1.50 g; 5.2 mmol), 4-bromo-butyricacid tert-butyl ester (1.38 g; 6.2 mmol) (prepared according to C.Morin, M. Vidal Tetrahedron, 1992, 48(42), 9277), potassium iodide (1.03g; 6.2 mmol), K₂CO₃ (1.42 g; 10.29 mmol), and CH₃CN (15 mL) were mixedand heated under reflux for 2 hours. After cooling to RT the reactionmixture was concentrated in vacuo, dissolved in EtOAc, washed with 5%aqueous NaHCO₃ solution, dried (Na₂SO₄) concentrated in vacuo andpurified by column chromatography (SiO₂, Et₂O:hexanes 1:1) to afford4-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester(1.90 g), TLC (SiO₂R_(f). 0.20 EtOAc:hexanes 1:1)

The following compounds were obtained according to a similar manner:

-   4-[2-(4-Octyl-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester-   4-[2-(4-Hexyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl    ester-   4-[2-(4-Heptyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl    ester-   {3-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-propyl}-phosphonic acid    diethyl ester-   4-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-butyric    acid tert-butyl ester

2,2-Dimethyl-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acidtert-butyl ester

The required 3-Chloro-2,2-dimethyl-propionic acid tert-butyl ester wasprepared as follows: To a solution of 3-chloro-2,2-dimethylpropionicacid (5.00 g; 36.6 mmol) in DMF (25 mL) was addedN,N′-carbonyldiimidazole (5.94 g; 36.6 mmol) and the resulting mixturewas stirred for 1 hour at 40° C. Subsequently, tert-butyl alcohol (7.1mL; 73 mmol) and DBU (5.5 mL; 36.6 mmol) were added and the mixturestirred overnight at 40° C. After cooling to RT, 5% aqueous NaHCO₃solution (50 mL) was added to the mixture and stirred for another 15minutes. The reaction mixture was extracted with EtOAc. The organiclayer was dried (Na₂SO₄), concentrated in vacuo and purified by columnchromatography (SiO₂, Et₂O:hexanes 1:1) to afford3-chloro-2,2-dimethyl-propionic acid tert-butyl ester (3.34 g).

3-[2-(4-Trifluoromethanesulfonyloxy-phenyl)-morpholin-4-yl]-propionicacid tert-butyl ester

To a solution of -[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester (2.07 g; 6.73 mmol) in CHCl₃ (50 mL) was added Et₃N(1.40 ml; 10.10 mmol), DMAP (82.3 mg; 0.67 mmol) andN-phenylbis(trifluoromethane-sulfonimide) (2.89 g; 8.08 mmol). Theresulting mixture was heated at 60° C. for 3 hours. After cooling to RTthe mixture was washed with 5% aqueous Na₂CO₃ and water. The organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, Et₂O) to afford3-[2-(4-trifluoromethanesulfonyloxy-phenyl)-morpholin-4-yl]-propionicacid tert-butyl ester (2.30 g).

3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid tert-butylester

To a degassed solution of3-[2-(4-trifluoromethanesulfonyloxy-phenyl)-morpholin-4-yl]-propionicacid tert-butyl ester (2.55 g; 5.80 mmol) in toluene (50 mL) was addedPd₂dba₃ (0.27 g; 0.29 mmol) and(2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]-ethyl]-2-(dicyclohexylphosphino)ferrocene(0.32 g; 0.58 mmol), followed, after 5 min. by, potassium thioacetate(1.33 g; 11.6 mmol). The resulting mixture was heated under refluxovernight. After cooling to RT the mixture was diluted with CH₂Cl₂,filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, CH₂Cl₂/acetone 95:5) to afford3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid tert-butylester (1.70 g)

3-{2-[4-(2,6-Dichloro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

A mixture of 3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionicacid tert-butyl ester (0.31 g; 0.85 mmol) and NaOH (37 mg, 0.93 mmol) inEtOH (10 mL) and water (1 mL) was stirred for 30 min at 0° C.Subsequently, 2,6-dichlorobenzyl bromide (0.22 g; 0.93 mmol), dissolvedin EtOH (2.5 mL), was added, and the mixture allowed to warm to RT.After 90 min. the mixture was partitioned between EtOAc and 5% aqueousNaHCO₃. The layers were separated, and the organic layer was washed with5% aqueous NaHCO₃ and brine, dried (Na₂SO₄), filtered and concentratedin vacuo. The residue was purified by column chromatography (SiO₂,CH₂Cl₂/acetone 95:5) to afford3-{2-[4-(2,6-dichloro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester (0.20 g).

The following compounds were obtained according to a similar manner:

-   3-{2-[4-(2-Chloro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester.-   3-{2-[4-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester.-   3-[2-(4-Octylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester.

3-[2-(4-Iodo-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester

To a solution of 3-[2-(4-bromo-phenyl)-thiomorpholin-4-yl]-propionicacid tert-butyl ester (22.15 g; 57.33 mmol) 1,4-dioxane (250 mL) wasadded N,N′-dimethylethylene-diamine (3.05 mL; 28.67 mmol). Through theresulting mixture was bubbled nitrogen gas for 1 hour, and subsequentlyCuI (1.09 g; 5.73 mmol), and NaI (21.48 g; 143.33 mmol) were added. Theresulting mixture was heated at 130° C. in a closed vessel for 4 days.After cooling to RT the mixture was concentrated in vacuo, and theresidue purified by column chromatography (SiO₂, Et₂O/hexanes 2:3) toafford 3-[2-(4-iodo-phenyl)-thiomorpholin-4-yl]-propionic acidtert-butyl ester (19.30 g)

3-[2-(4-Benzyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butylester

(All solutions were degassed) To a suspension of 1,10-phenanthroline(183.0 mg; 1.02 mmol) in toluene (15 mL) was added CuI (96.7 mg; 0.51mmol), Cs₂CO₃ (3.31 g; 10.15 mmol), and a solution of3-[2-(4-iodo-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester(2.20 g; 5.08 mmol) and benzyl alcohol (1.05 mL; 10.15 mmol) in toluene(20 mL). The resulting mixture was heated for three days at 100° C.After cooling to RT EtOAc and water were added. The layers wereseparated and the organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, EtOAc/CH₂Cl₂ 1:6) to afford3-[2-(4-benzyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butylester (1.85 g).

The following compounds were obtained according to a similar manner:

-   3-{2-[4-(2-Chloro-benzyloxy)-phenyl]-thiomorpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-thiomorpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(4-Octyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid    tert-butyl ester

3-[2-(4-Benzyloxy-phenyl)-1-oxo-thiomorpholin-4-yl]-propionic acidtert-butyl ester

To a solution of 3-[2-(4-benzyloxy-phenyl)-thiomorpholin-4-yl]-propionicacid tert-butyl ester (0.85 g; 1.77 mmol) in MeOH (25 mL) was addeddropwise a solution of Oxone® (0.54 g; 0.89 mmol) in water (25 mL), at0° C. The resulting mixture was stirred for 2 hours at 0° C., andsubsequently, overnight at RT. The resulting mixture was treated withwater and a 25% aqueous solution of NH₄OH, and extracted with EtOAc. Thecombined organic layers were dried (MgSO₄), filtered, and concentratedin vacuo. The residue was purified by column chromatography (SiO₂,CH₂Cl₂/MeOH 97.5:2.5) to afford3-[2-(4-benzyloxy-phenyl)-1-oxo-thiomorpholin-4-yl]-propionic acidtert-butyl ester (0.65 g).

The following compounds were obtained according to a similar manner:

-   3-{2-[4-(2-Chloro-benzyloxy)-phenyl]-1-oxo-thiomorpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-1-oxo-thiomorpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(4-Octyloxy-phenyl)-1-oxo-thiomorpholin-4-yl]-propionic acid    tert-butyl ester

{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-acetic acid ethylester

A mixture of 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholinehydrochloride (0.65 g; 1.68 mmol), Et₃N (0.58 mL; 4.2 mmol), and ethylbromoacetate (0.24 ml; 2.19 mmol) in CH₃CN (65 mL) was stirred at 85°C., overnight. After cooling to RT the mixture was concentrated in vacuoand the residue partitioned between water and CH₂Cl₂. The layers wereseparated and aqueous layer was extracted once more with CH₂Cl₂. Thecombined organic layers were concentrated in vacuo and the residue waspurified by column chromatography (SiO₂, Et₂O:hexanes 2:1) to afford{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-acetic acid ethylester (0.62 g).

2,2-Difluoro-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acidethyl ester

To a solution of 2-(4-octyloxy-phenyl)-morpholine (0.75 g; 2.6 mmol) inEtOH (10 mL) was added 1H-benzotriazole-1-methanol (0.38 g; 2.6 mmol),and the reaction mixture was heated at 50° C. for 20 minutes. Aftercooling to RT, the solvent was removed in vacuo to afford1-[H-2-(4-octyloxy-phenyl)-morpholin-4-ylmethyl]-1H-benzotriazole; whichwas used as such.

To a suspension of zinc dust (0.34 g; 5.2 mmol) in dry THF (10 mL) wasadded chlorotrimethylsilane (0.33 mL; 2.6 mmol) and ethylbromodifluoroacetate (0.50 ml; 3.9 mmol), this mixture was heated underreflux for 10 min. and then cooled to RT. To the resulting mixture wasadded drop-wise a solution of1-[2-(4-octyloxy-phenyl)-morpholin-4-ylmethyl]-1H-benzotriazole in THF(5 mL). After the addition is complete the resulting mixture is heatedunder efflux for 2 hours. After cooling to RT the reaction mixture wasfiltered over Kieselguhr and the filter-cake was washed with ethanol.The solvents were removed in vacuo and the residue was purified bycolumn chromatography (SiO₂, Et₂O:hexanes 1:1) to afford2,2-difluoro-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acidethyl ester (0.58 g).

3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-difluoro-propionicacid ethyl ester was obtained according to a similar manner.

3-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-3-oxo-propionic acid ethylester

To a suspension of 2-(4-octyloxy-phenyl)-morpholine (0.97 g; 3.3 mmol)and N-ethyldiisopropylamine (1.14 ml; 6.7 mmol) in CH₃CN (10 mL) wasadded dropwise ethyl malonyl chloride (0.51 ml; 4.0 mmol). The resultingmixture was stirred for one hour at RT and subsequently partitionedbetween 5% aqueous NaHCO₃ solution and Et₂O. The organic layer was dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, Et₂O) to afford3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-3-oxo-propionic acid ethylester (0.50 g).

3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-3-oxo-propionicacid ethyl ester was obtained according to a similar manner.

2-Methyl-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester

To a suspension of 2-(4-octyloxy-phenyl)-morpholine hydrochloride (0.17g; 0.5 mmol) in DMF (5.00 mL) was added tert-butyl methacrylate (0.17mL; 1.0 mmol) and DBU (0.23 mL; 1.5 mmol) The resulting mixture washeated at 140° C. in a sealed flask overnight. After cooling to RT thereaction mixture was partitioned between 5% aqueous NaHCO₃ solution andEtOAc. The layers were separated and the organic layer was dried(Na₂SO₄), filtered, and concentrated. The residue was purified by columnchromatography (SiO₂, Et₂O:hexanes 1:1) to afford2-methyl-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester (0.11 g).

3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2-methyl-propionicacid tert-butyl ester was obtained according to a similar manner.

3-[2-(4-Octyloxy-phenyl)-morpholin-4.-yl]-butyric acid tert-butyl ester

A mixture of 2-(4-octyloxy-phenyl)-morpholine (0.24 gram, 1.1 mmol),3-bromobutyric acid tert-butyl ester (0.24 g; 1.1 mmol), sodium iodide(27.4 mg; 0.2 mmol), and DBU (0.4 mL; 2.7 mmol) in CH₃CN (10 mL) washeated in a closed vessel at 120° C. After cooling to RT the reactionmixture was partitioned between 5% aqueous NaHCO₃ solution and EtOAc.The layers were separated and the organic layer was dried (Na₂SO₄),filtered, and concentrated. The residue was purified by columnchromatography (SiO₂, Et₂O) to afford3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester(0.15 g).

3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-butyric acidtert-butyl ester was obtained according to a similar manner. Therequired 3-bromobutyric acid tert-butyl ester was prepared as follows:To a solution of 3-bromobutyric acid (5.0 mL; 47.0 mmol) intetrahydrofuran (50 mL) was added dropwise trifluoroacetic anhydride(13.7 mL; 98.7 mmol) at −40° C. After 1 hour at −40° C. tert-butylalcohol (20 mL) was added. The resulting mixture was allowed to warm toRT and stirred overnight. Subsequently, the reaction mixture wasconcentrated in vacuo. The residue was treated with 2M aqueous NaOHsolution and extracted with Et₂O. The organic layer was dried (Na₂SO₄),and concentrated in vacuo to afford 3-bromobutyric acid tert-butyl ester(6.05 g), which was used as such.

3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionicacid methyl ester

To a solution of 2,2-dimethyl-3-oxo-propionic acid methyl ester(WHSS0374-001) (0.90 g; 5.44 mmol) in 1,2-dichloroethane (20 mL) wasadded 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.91 g, 2.7mmol) and NaBH(OAc)3 (1.62 g; 7.62 mmol). The resulting mixture wasstirred overnight at RT, and subsequently treated with 5% aqueous NaHCO₃(10 mL) and extracted with CH₂Cl₂ (3×30 ml). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, Et₂O/hexanes 1:1) to afford3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionicacid methyl ester (1.12 g) as a clear colourless oil. The required2,2-dimethyl-3-oxo-propionic acid methyl ester was prepared as follows:To a solution of 2,2-dimethyl-3-hydroxypropionic acid methyl ester(10.00 g; 75.7 mmol) in CH₂Cl₂ (200 mL) was added pyridiniumchloroformate (28.54 g; 132.4 mmol) in small portions, at 0° C. Thereaction mixture was allowed to slowly warm to RT and stirred overnight.Subsequently, the mixture was diluted with CH₂Cl₂, filtered overkieselguhr, and concentrated in vacuo. The remaining oil was purified bycolumn chromatography (SiO₂, hexanes/Et₂O 7:3) to afford2,2-dimethyl-3-oxo-propionic acid methyl ester (5.59 g)

The following compound was made according to a similar method:

3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-cyclobutanecarboxylicacid tert-butyl ester

The required 3-oxo-cyclobutanecarboxylic acid tert-butyl ester wasprepared as described in: R. P. Lemieux, G. B. Schuster, J. Org. Chem.,1993, 58, 100.

3-{2-[4-(Benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butylester

A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester) (76.8 mg; 0.25 mmol), Cs₂CO₃ (241 mg; 0.74 mmol), andNaI (3.7 mg, 25 μmol) in CH₃CN/THF (6:4; 2.5 mL) was stirred for threehours at RT. Subsequently, benzyl chloride (35 μL; 0.3 mmol) in CH₃CN (1mL) was added and the resulting mixture was heated at 60° C., for 20 h.After cooling to RT the solvents were removed in vacuo. The residue waspartitioned between CH₂Cl₂ and 1M aqueous K₂CO₃. The layers wereseparated and the aqueous layer washed with CH₂Cl₂. The combined organiclayers were concentrated in vacuo, and the residue dried under vacuum,at 40° C., overnight. The obtained product was used as such in the nextstep.

The following compounds were obtained according to a similar manner:

-   3-{2-[4-(6-Methyl-imidazo[1,2-a]pyridin-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-(2-{4-[3-(2-Propyl-thiazol-5-yloxy)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-{2-[4-(2-Benzyloxy-ethoxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(2-Phenoxy-ethoxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-[2-(4-Hex-5-ynyloxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-{2-[4-(4-Acetoxy-butoxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-(2-{4-[3-(4-Fluoro-phenoxy)-propoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-(2-{4-[2-(Naphthalen-2-yloxy)-ethoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-[2-(4-Phenylcarbamoylmethoxy-phenyl)-morpholin-4-yl]-propionic    acid tert-butyl ester-   3-{2-[4-(4-Pyrazol-1-yl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(1-Methyl-1H-pyrazol-3-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Chloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(6-Cyano-hexyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-[2-(4-Phenethyloxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-{2-[4-(3-Phenyl-propoxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(3-Benzyloxy-propoxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(7-Methoxy-heptyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-(2-{4-[3-(4-tert-Butyl-phenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester-   3-{2-[4-(5-Oxo-hexyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(4-Phenyl-butoxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(3-Methoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(2-Chloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-[2-(4-Cyclohexylmethoxy-phenyl)-morpholin-4-yl]-propionic acid    tert-butyl ester-   3-{2-[4-(2-Benzenesulfonyl-ethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Phenoxy-propoxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(4-[1,2,4]Triazol-1-yl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,3-Dihydro-benzofuran-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Biphenyl-4-yl-2-oxo-ethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Phenoxy-butoxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(2-Oxo-2-phenyl-ethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Chloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-(2-{4-[2-(1H-Indol-3-yl)-ethoxy]-phenyl}-morpholin-4-yl)-propionic    acid tert-butyl ester

3-{2-[4-(3-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

To a solution of (3-methoxybenzyl alcohol (0.25M, 450 μl) in THF wasadded a solution of3-[2-(4-hydroxy-2-methyl-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester (0.25M, 360 μl) in THF. To this mixture a solution ofDIAD in THF (0.25M, 360 μl) was added. Finally, polystyrene supportedtriphenylphosphine (˜190 mg, 1.2 mmol/g) was added followed by THF (1mL). The reaction mixture was shaken with interval for 20 hours at 30°C. Subsequently, more DIAD (360 μl, 0.25M in THF) and polystyrenesupported triphenylphosphine (95 mg, 1.2 mmol/g) were added. The mixturewas shaken again with interval for 20 hours at 30° C. To the resultingmixture was added macroporous carbonate resin (˜90 mg, 3.06 mmol/g,Argonaut Technologies) and the mixture was shaken again with intervalfor 20 hours at 50° C.

The mixture was transferred to a Methanol and THF conditioned StrongCationic Exchange cartridge (1ST, 0.5 g, 0.6 mmol/g), washed with THF (6ml) and CH₃CN (8 ml) consecutively before being eluted with 1N NH₄OH inCH₃CN (6 ml). Concentration in vacuo afforded3-{2-[4-(3-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester (˜15 mg), which was used as such.

The following compounds were obtained according to a similar manner:

-   3-{2-[4-(5-Bromo-2-methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,4-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,3-Dimethoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(4-Cyclopentylmethoxy-2-methyl-phenyl)-morpholin-4-yl]-propionic    acid tert-butyl ester-   3-{2-[4-(2,5-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(pyridin-3-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(naphthalen-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(Benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic acid    tert-butyl ester-   3-{2-[4-(2-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(6-methyl-pyridin-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,5-Dimethoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Bromo-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(Biphenyl-2-ylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3,5-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(3-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Chloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Isopropyl-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(3-phenoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(2-phenethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3,4-Dimethoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3,5-Dimethyl-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Benzyloxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(thiophen-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Fluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Benzyloxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Fluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(Biphenyl-4-ylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(pyridin-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Butoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-[2-(4-Cyclohexylmethoxy-2-methyl-phenyl)-morpholin-4-yl]-propionic    acid tert-butyl ester-   3-{2[2-Methyl-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(3-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,3-Difluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(4-trifluoromethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Chloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2[2-Methyl-4-(tetrahydro-pyran-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2[2-Methyl-4-(4-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3,4-Difluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(2,3,4-trimethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(Cyclohex-3-enylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Butyl-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(4-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Dimethylamino-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(pyridin-4-ylmethoxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2-Iodo-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3,5-Dimethoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,4-Difluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(2,4,5-trimethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(3-Bromo-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-Bromo-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(4-tert-Butyl-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[4-(2,5-Difluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic    acid tert-butyl ester-   3-{2-[2-Methyl-4-(tetrahydro-furan-3-ylmethoxy)-phenyl]-morpholin-4yl}-propionic    acid tert-butyl ester

3-{2-[4-(2,6-Dichloro-4-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester

3-{2-[4-(2,6-Dichloro-4-iodo-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester (0.34 g; 0.57 mmol), and Pd(dppf)Cl₂ (14.70 mg;0.02 mmol) were added to a solution of lithium chloride (4.59 ml; 0.50mol/1; 2.30 mmol) in THF; 0.04 eq.). The resulting mixture was cooled to0° C. and a solution of diethylzinc in n-heptane (1.15 ml; 1.00 mol/l;1.15 mmol) was added dropwise. The mixture was heated to 60° C.overnight. After cooling to RT saturated aqueous NH₄Cl was added. Themixture was extracted with EtOAc. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO2, EtOAc:hexanes 1:1) to afford3-{2-[4-(2,6-dichloro-4-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester (115.00 mg)

2-(4-Octyloxy-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-morpholine

A mixture of 2-(4-octyloxy-phenyl)-morpholine (1.99 g; 6.8 mmol),2-(2-chloroethoxy)-tetrahydro-2H-pyran (1.21 ml; 8.2 mmol), K₂CO₃ (1.89g; 13.7 mmol) and NaI (0.20 g; 1.4 mmol) in DMF (15 mL) was heated to100° C. overnight. After cooling to RT the reaction mixture waspartitioned between 5% aqueous NaHCO₃ solution and Et₂O. The organiclayer was dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, EtOAc) to afford2-(4-octyloxy-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-morpholine(2.04 g).

2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-morpholinewas obtained according to a similar manner.

{2-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-ethyl}-phosphonic acid diethylester

A mixture of 2-(4-octyloxy-phenyl)-morpholine (0.83 g; 2.9 mmol) anddiethyl vinylphosphonate (0.53 ml; 3.4 mmol) in CH₃CN (10 mL) was heatedunder reflux for 3 days. After cooling to RT the mixture wasconcentrated in vacuo and the residue was purified by columnchromatography (SiO₂, EtOAc: MeOH 90:10) to afford{2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl}-phosphonic acid diethylester (0.42 g)

Phosphoric acid di-tert-butyl ester2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl ester

To a solution of 2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethanol (1.33g; 4.0 mmol) in a mixture of THF (15 mL) and CH₂Cl₂ (15 mL) was added atetrazole solution in CH₃CN (17.6 mL; 0.45 mol/L; 7.9 mmol) at RT. Theresulting mixture was stirred for 30 minutes and subsequentlydi-tert-butyl N,N-diisopropylphosphoramidite (2.00 ml; 6.3 mmol) wasadded and stirred overnight at RT. Subsequently, an aqueous hydrogenperoxide solution (1.80 ml; 300 g/1; 15.9 mmol) was added and themixture stirred at RT for another 15 min. The reaction was quenched bythe addition of an 5% aqueous NaHCO₃ solution and extracted with EtOAc.The organic layer was dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by column chromatography (SiO₂, Et₂O) toafford phosphoric acid di-tert-butyl ester2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl ester (0.71 g).

Phosphoric acid di-tert-butyl ester2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethyl ester

To a solution of2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethanol (0.74g; 1.94 mmol) in a mixture of THF (10 mL) and CH₂Cl₂ (10 mL) was added atetrazole solution in CH₃CN ((8.60 ml; 0.45 mol/1; 3.87 mmol) at RT. Theresulting mixture was stirred for 30 minutes and subsequentlydi-tert-butyl N,N-diisopropylphosphoramidite (0.98 ml; 3.10 mmol) wasadded and stirred overnight at RT. Subsequently, the mixture was cooledto 4° C., and a solution of tert-butyl hydroperoxide in nonane (0.31 ml;˜5.5 mol/L, 2.90 mmol) was added. Thereafter the mixture was stirred atRT for another 30 min. The reaction was quenched by the addition of an5% aqueous NaHCO₃ solution and extracted with EtOAc. The organic layerwas dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, EtOAc) to afford phosphoricacid di-tert-butyl ester2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethyl ester(0.66 g).

{2-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-propyl}-phosphonic aciddiethyl ester

A mixture of 2-(4-octyloxy-phenyl)-morpholine (1.04 g; 3.6 mmol),diethyl (3-bromopropyl)phosphonate (0.82 mL; 4.3 mmol), NaI (0.11 g; 0.7mmol), and K₂CO₃ (0.99 g; 7.1 mmol) in CH₃CN (10 mL) was heated underreflux for 2 hours. After cooling to RT the mixture was partitionedbetween 5% aqueous NaHCO₃ solution and Et₂O. The organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby column chromatography (SiO₂, EtOAc: MeOH 90:10) to afford{2-[2-(4-octyloxy-phenyl)morpholin-4-yl]-propyl}-phosphonic acid diethylester (1.13 g).

(3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propyl)-phosphonicacid diethyl ester was obtained according to a similar manner.

§4. SYNTHESES OF SPECIFIC COMPOUNDS See Tables Method A Compound 1(3-{2-[4-(benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid)

The crude 3-{2-[4-(benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtert-butyl ester (see §3) was treated with a mixture of TFA, water, andCH₂Cl₂ (30:3:67; 3 mL) and stirred at RT for 2 h. Subsequently, thevolatiles were removed in vacuo, and the crude product was purified bypreparative HPLC to afford3-{2-[4-(benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt; R_(t)=1.86 min. (System A), [M+H]⁺ Found:342.19; Calc: 342.17. Conditions for the preparative LC-MS: Injection ofthe crude product dissolved in 600 L DMSO/CH₃CN 1:2; column WatersSunfire 19×100 mm 5 μm 45° C., mobile phase water/CH₃CN/TFA 0.1% 25mL/min, run 20 min 10%-90% CH₃CN, detection with UV 210-260 nm.

The following compounds were obtained similarly:

Compound 2;3-{2-[4-(6-Methyl-imidazo[1,2-a]pyridin-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=0.76 min. (System A), [M+H]⁺ Found: 396.23; Calc: 396.19.

Compound 3;3-(2-{4-[3-(2-Propyl-thiazol-5-yloxy)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid trifluoroacetic acid salt

R_(t)=2.04 min. (System A), [M+H]⁺ Found: 435.21; Calc: 435.20.

Compound 4;3-{2-[4-(2-Benzyloxy-ethoxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=1.89 min. (System A), [M+H]⁺ Found: 386.22; Calc: 386.20.

Compound 5; 3-{2-[4-(2-Phenoxy-ethoxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=1.91 min. (System A), [M+H]⁺ Found: 372.21; Calc: 372.18.

Compound 6; 3-[2-(4-Hex-5-ynyloxy-phenyl)-morpholin-4-yl]-propionic acidtrifluoroacetic acid salt

R_(t)=1.77 min. (System A), [M+H]⁺ Found: 332.21; Calc: 332.19.

Compound 7; 3-{2-[4-(4-Acetoxy-butoxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=1.51 min. (System A), [M+H]⁺ Found: 366.21; Calc: 366.19.

Compound 8;3-(2-{4-[3-(4-Fluoro-phenoxy)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid trifluoroacetic acid salt

R_(t)=2.16 min. (System A), [M+H]⁺ Found: 404.22; Calc: 404.19.

Compound 9;3-(2-{4-[2-(Naphthalen-2-yloxy)-ethoxy]-phenyl}-morpholin-4-yl)-propionicacid trifluoroacetic acid salt

R_(t)=2.35 min. (System A), [M+H]⁺ Found: 422.24; Calc: 422.20.

Compound 10;3-[2-(4-Phenylcarbamoylmethoxy-phenyl)-morpholin-4-yl]-propionic acidtrifluoroacetic acid salt

R_(t)=1.48 min. (System A), [M+H]⁺ Found: 385.20; Calc: 385.18.

Compound 11;3-{2-[4-(4-Pyrazol-1-yl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=1.83 min. (System A), [M+H]⁺ Found: 408.22; Calc: 408.19.

Compound 12;3-{2-[4-(1-Methyl-1H-pyrazol-3-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=1.14 min. (System A), [M+H]^(+Found:) 346.20; Calc: 346.18.

Compound 13;3-{2-[4-(4-Chloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=2.14 min. (System A), [M+H]⁺ Found: 376.13; Calc: 376.13.

Compound 14;3-{2-[4-(6-Cyano-hexyloxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=1.68 min. (System A), [M+H]⁺ Found: 361.24; Calc: 361.21.

Compound 15; 3-[2-(4-Phenethyloxy-phenyl)-morpholin-4-yl]-propionic acidtrifluoroacetic acid salt

R_(t)=1.93 min. (System A), [M+H]⁺ Found: 356.23; Calc: 356.19.

Compound 16;3-{2-[4-(3-Phenyl-propoxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=2.11 min. (System A), [M+H]⁺ Found: 370.24; Calc: 370.20.

Compound 17;3-{2-[4-(3-Benzyloxy-propoxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=1.97 min. (System A), [M+H]⁺ Found: 400.26; Calc: 400.21.

Compound 18;3-{2-[4-(7-Methoxy-heptyloxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=2.04 min. (System A), [M+H]⁺ Found: 380.27; Calc: 380.24.

Compound 19;3-(2-{4-[3-(4-tert-Butyl-phenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-morpholin-4-yl)-propionicacid trifluoroacetic acid salt

R_(t)=2.67 min. (System A), [M+H]⁺ Found: 466.27; Calc: 466.23.

Compound 20; 3-{2-[4-(5-Oxo-hexyloxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=1.35 min. (System A), [M+H]⁺ Found: 350.22; Calc: 350.20.

Compound 21; 3-{2-[4-(4-Phenyl-butoxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=2.38 min. (System A), [M+H]⁺ Found: 384.25; Calc: 384.22.

Compound 22;3-{2-[4-(3-Methoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=1.75 min. (System A).

Compound 23;3-{2-[4-(2-Chloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=1.99 min. (System A), [M+H]⁺ Found: 376.18; Calc: 376.13.

Compound 24; 3-[2-(4-Cyclohexylmethoxy-phenyl)-morpholin-4-yl]-propionicacid trifluoroacetic acid salt

R_(t)=2.26 min. (System A), [M+H]⁺ Found: 348.27; Calc: 348.22.

Compound 25;3-{2-[4-(2-Benzenesulfonyl-ethoxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=1.45 min. (System A), [M+H]⁺ Found: 420.18; Calc: 420.15.

Compound 26;3-{2-[4-(3-Phenoxy-propoxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=2.12 min. (System A), [M+H]⁺ Found: 386.21; Calc: 386.20.

Compound 27;3-{2-[4-(4-[1,2,4]Triazol-1-yl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=1.46 min. (System A), [M+H]⁺ Found: 409.22; Calc: 409.19.

Compound 28;3-{2-[4-(2,3-Dihydro-benzofuran-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=1.94 min. (System A), [M+H]⁺ Found: 384.21; Calc: 384.18.

Compound 29;3-{2-[4-(2-Biphenyl-4-yl-2-oxo-ethoxy)-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

R_(t)=2.30 min. (System A), [M+H]⁺ Found: 446.23; Calc: 446.20.

Compound 30;3-{2-[4-(4-Phenoxy-butoxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=2.25 min. (System A), [M+H]⁺ Found: 400.24; Calc: 400.21.

Compound 31;3-{2-[4-(2-Oxo-2-phenyl-ethoxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=1.60 min. (System A), [M+H]⁺ Found: 370.18; Calc: 370.17.

Compound 32;3-{2-[4-(3-Chloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtrifluoroacetic acid salt

R_(t)=2.09 min. (System A), [M+H]⁺ Found: 376.16; Calc: 376.13.

Compound 33;3-(2-{4-[2-(1H-Indol-3-yl)-ethoxy]-phenyl}-morpholin-4-yl)-propionicacid trifluoroacetic acid salt

R_(t)=1.99 min. (System A), [M+H]⁺ Found: 395.22; Calc: 395.20.

Method B Compound 34;3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid

3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidtert-butyl ester (0.59 g; 1.27 mmol) was dissolved in a 4M solution ofHCl in 1,4-dioxane (6.33 mL, 25.30 mmol) and stirred overnight at RT.Subsequently, the solvent was removed in vacuo and the residue treatedwith iPr₂O, the precipitate was collected by filtration and driedovernight under reduced pressure to afford3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride (0.50 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.88-2.97 (2H,m) 3.11 (1H, t, J=11.7 Hz) 3.15-3.23 (1H, m) 3.30-3.43 (2H, m) 3.49 (1H,d, J=12.0 Hz) 3.55-3.64 (1H, m) 4.01-4.20 (2H, m) 4.88 (1H, d, J=12.0Hz) 5.24 (2H, s) 7.04-7.12 (2H, m) 7.35 (2H, d, J=8.7 Hz) 7.40-7.49 (1H,m) 7.49-7.56 (2H, m).

The following compounds were obtained according to a similar manner:

Compound 34a;(+)-3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

([α]_(D) ²⁵=+7 (c 1.0, MeOH)). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.82-2.96(m, 2H) 3.09 (d, J=0.37 Hz, 2H) 3.34 (br. s., 2H) 3.43-3.52 (m,1H3.95-4.07 (m, 1H) 4.09-4.20 (m, 1H) 4.78-4.88 (m, 1H) 5.24 (s, 2H)7.06-7.14 (m, 2H) 7.30-7.39 (m, 2H) 7.43-7.51 (m, 1H) 7.54-7.62 (m, 2H)

Compound 34b;(−)-3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

([α]_(D) ²⁵=−7 (c 1.0, MeOH)). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84-2.96(m, 2H) 3.09 (s, 2H) 3.34 (br. s., 2H) 3.43-3.52 (m, 1H) 3.97-4.08 (m,1H) 4.09-4.18 (m, 1H) 4.79-4.89 (m, 1H) 5.24 (s, 2H) 7.07-7.15 (m, 2H)7.31-7.38 (m, 2H) 7.43-7.51 (m, 1H) 7.54-7.60 (m, 2H).

Compound 35; 3-(2-(4-Octyl-phenyl)-morpholin-4-yl)-propionic acidhydro-chloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.55-0.71 (m, 3H) 1.04 (br, 10H)1.25-1.43 (m, 2H) 2.23-2.44 (m, 2H) 2.55-2.73 (m, 2H) 2.78-3.04 (m, 2H)3.08-3.53 (m, 4H) 3.67-4.07 (m, 2H) 4.48-4.69 (m, 1H) 6.90-7.25 (m, 4H).

Compound 36; 4-[2-(4-Octyl-phenyl)-morpholin-4-yl]-butyric acidhydro-chloride

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.86 (t, J=6.8 Hz, 3H) 1.19-1.33 (m,10H) 1.52-1.60 (m, 2H) 1.94-2.02 (m, 2H) 2.36 (t, J=7.2 Hz, 2H) 2.57 (t,J=7.7 Hz, 2H) 3.03-3.18 (m, 4H) 3.58-3.68 (m, 2H) 4.10-4.19 (m, 2H)4.84-4.89 (m, 1H) 7.22 (d, J=8.6 Hz, 2H) 7.30 (d, J=8.6 Hz, 2H).

Compound 37; 3-[2-(4-Hexyloxy-phenyl)-morpholin-4-yl]-propionic acidhydro-chloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-0.91 (m, 3H) 1.27-1.34 (m, 4H)1.36-1.46 (m, 2H) 1.66-1.74 (m, 2H) 2.84-2.91 (m, 2H) 3.02-3.18 (m, 2H)3.30-3.40 (m, 2H) 3.44-3.51 (m, 1H) 3.52-3.61 (m, 1H) 3.91-4.02 (m, 3H)4.09-4.17 (m, 1H) 4.74-4.81 (m, 1H) 6.95 (d, J=8.7 Hz, 2H) 7.29 (d,J=8.7 Hz, 2H) 11.10-12.90 (m, 2H).

Compound 38; 4-[2-(4-Hexyloxy-phenyl)-morpholin-4-yl]-butyric acidhydro-chloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.63-0.71 (m, 3H) 1.05-1.15 (m, 4H)1.15-1.25 (m, 2H) 1.44-1.53 (m, 2H) 1.70-1.81 (m, 2H) 2.14 (t, J=7.1 Hz,2H) 2.78-2.95 (m, 2H) 3.11-3.39 (m, 4H) 3.75 (t, J=6.4 Hz, 2H) 3.78-3.84(m, 1H) 3.87-3.96 (m, 1H) 4.56-4.64 (m, 1H) 6.75 (d, J=8.7 Hz, 2H) 7.09(d, J=8.7 Hz, 2H) 10.70-11.00 (bs, 1H).

Compound 39; 3-[2-(4-Heptyloxy-phenyl)-morpholin-4-yl]-propionic acidhydro-chloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.59-0.68 (m, 3H) 0.96-1.22 (m, 8H)1.40-1.52 (m, 2H) 2.61-2.72 (m, 2H) 2.78-2.96 (m, 2H) 3.02-3.39 (m, 4H)3.67-3.81 (m, 3H) 3.84-3.94 (m, 1H) 4.57 (d, J=10.8 Hz, 1H) 6.71 (d,J=8.7 Hz, 2H) 7.05 (d, J=8.7 Hz, 2H) 10.67-12.94 (m, 2H).

Compound 40; 4-[2-(4-Heptyloxy-phenyl)-morpholin-4-yl]-butyric acidhydro-chloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (t, J=7.0 Hz, 3H) 1.22-1.35 (m, 6H)1.36-1.44 (m, 2H) 1.66-1.74 (m, 2H) 1.94-2.05 (m, 2H) 2.34 (t, J=7.4 Hz,2H) 2.99-3.17 (m, 4H) 3.43-3.57 (m, 2H) 3.95 (t, J=6.4 Hz, 2H) 4.03-4.14(m, 2H) 4.87 (d, J=10.2 Hz, 1H) 6.94 (d, J=8.7 Hz, 2H) 7.29 (d, J=8.7Hz, 2H) 10.80-11.20 (bs, 1H) 12.00-12.40 (bs, 1H).

Compound 41; 3-(2-(4-Octyloxy-phenyl)-morpholin-4-yl)-propionic acidhydro-chloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.36 (8H, m) 1.37-1.46 (2H, m)1.66-1.77 (2H, m) 2.85-2.92 (2H, m) 3.08 (1H, t, J=11.7 Hz) 3.13-3.21(1H, m) 3.29-3.41 (2H, m) 3.48 (1H, d) 3.56 (1H, d, J=12.3 Hz) 3.95 (2H,t, J=6.5 Hz) 4.01 (1H, t, J=12.2 Hz) 4.07-4.17 (1H, m) 4.80 (1H, d,J=10.8 Hz) 6.92 (2H, dt, J=8.5, 0.7 Hz) 7.28 (2H, d, J=9.0 Hz).

Compound 41a; (+)-3-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-propionicacid hydrochloride

from Isomer 2 of 3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester, [α]_(D) ²⁵=+5 (c 1.0, MeOH); ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.81-0.92 (m, 3H) 1.19-1.47 (m, 10H) 1.64-1.77 (m, 2H) 2.83-2.96(m, 2H) 3.03-3.21 (m, 2H) 3.29-3.40 (m, 2H) 3.48 (d, J=12.34 Hz, 1H)3.56 (d, J=12.34 Hz, 1H) 3.95 (t, J=6.47 Hz, 2H) 3.98-4.08 (m, 1H)4.08-4.18 (m, 1H) 4.75-4.87 (m, 1H) 6.88-6.97 (m, 2H) 7.28 (d, J=8.73Hz, 2H)

Compound 41 b; (−)-3-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-propionicacid hydrochloride

from Isomer 1 of 3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acidtert-butyl ester, [α]₀ ²⁵=−5 (c 1.0, MeOH); ¹H NMR (400 MHz, DMSO-d₆) δppm 0.57-0.76 (m, 3H) 0.93-1.31 (m, 10H) 1.40-1.58 (m, 2H) 2.61-2.80 (m,2H) 2.80-3.01 (m, 2H) 3.13 (t, J=7.83 Hz, 2H) 3.20-3.45 (m, 2H)3.65-4.01 (m, 4H) 4.63 (m, 1H) 6.65-6.87 (m, 2H) 7.09 (d, J=8.73 Hz, 2H)

Compound 42; 4-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-butyric acidhydro-chloride

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.86 (t, J=6.8 Hz, 3H) 1.21-1.34 (m, 8H)1.36-1.44 (m, 2H) 1.66-1.74 (m, 2H) 1.95-2.05 (m, 2H) 2.36 (t, J=7.2 Hz,2H) 3.03-3.19 (m, 4H) 3.47-3.59 (m, 2H) 3.95 (t, J=6.4 Hz, 2H) 4.02-4.20(m, 2H) 4.86 (d, J=10.2 Hz, 1H) 6.93 (d, J=8.7 Hz, 2H) 7.30 (d, J=8.7Hz, 2H) 11.23-11.40 (bs, 1H).

Compound 43;2,2-Dimethyl-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.64 (t, J=6.32 Hz, 3H) 0.86-1.25 (m,17H) 1.42-1.53 (m, J=6.96, 6.96, 6.85, 6.62 Hz, 2H) 3.68-3.99 (m, 4H)4.73 (d, J=10.53 Hz, 1H) 6.72 (d, 2H) 7.06 (d, J=7.83 Hz, 2H).

Compound 44; 3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acidhydro-chloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79-0.86 (m, 4H) 1.17-1.42 (m, 16H)1.63-1.72 (m, 2H) 3.93 (t, J=6.47 Hz, 3H) 4.11-4.19 (m, 1H) 4.65-4.73(m, 1H) 6.91 (d, J=8.73 Hz, 2H) 7.31 (d, J=8.43 Hz, 2H).

Compound 45; 2-Methyl-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.67 (t, J=6.47 Hz, 2H) 1.05 (dd,J=7.22, 3.91 Hz, 4H) 1.03 (br. s., 2H) 1.09 (br. s., 3H) 1.19 (d, J=7.52Hz, 2H) 1.50 (qd, J=6.92, 6.62 Hz, 1H) 2.31 (br. s., 3H) 2.85-2.93 (m,2H) 2.95 (br. s., 1H) 3.18 (br. s., 7H) 3.26 (br. s., 2H) 3.29 (br. s.,1H) 3.37 (s, 1H) 3.76 (t, J=6.47 Hz, 1H) 3.90 (br. s., 1H) 6.75 (d,J=8.43 Hz, 1H) 7.08 (dd, J=8.43, 6.32 Hz, 1H).

Compound 46;3-{2-[4-(2-Chloro-6-fluorobenzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 1H) 2.82-2.98 (m, 2H) 3.02-3.20(m, 2H) 3.26-3.40 (m, 2H) 3.47 (d, J=12.04 Hz, 1H) 3.93-4.07 (m, 1H)4.08-4.21 (m, 1H) 4.75-4.91 (m, 1H) 5.16 (dd, J=1.35, 0.75 Hz, 2H)7.02-7.17 (m, 1H) 7.28-7.39 (m, 2H) 7.40-7.46 (m, 1H) 7.48-7.57 (m, 1H).

Compound 47;3-{2-[4-(2-Trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (s, 1H) 2.81-2.96 (m, 2H) 3.01-3.20(m, 2H) 3.24-3.39 (m, 2H) 3.47 (d, J=12.64 Hz, 1H) 3.53-3.64 (m, 1H)3.92-4.06 (m, 1H) 4.08-4.19 (m, 1H) 4.80 (d, J=11.14 Hz, 1H) 5.24 (s,2H) 7.00-7.09 (m, 2H) 7.28-7.38 (m, 2H) 7.54-7.64 (m, 1H) 7.68-7.84 (m,2H).

Compound 48;3-{2-[4-(2,6-Difluoro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

1H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (s, 1H) 2.85-2.99 (m, 2H) 3.03-3.22(m, 2H) 3.25-3.40 (m, 2H) 3.47 (d, J=12.04 Hz, 1H) 3.95-4.08 (m, 1H)4.10-4.19 (m, 1H) 4.78-4.91 (m, 1H) 5.13 (s, 2H) 7.08 (d, J=8.73 Hz, 2H)7.15-7.25 (m, 2H) 7.34 (d, J=8.73 Hz, 2H) 7.48-7.60 (m, 1H).

Compound 49;3-{2-[4-(3-Trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.83-2.94 (1H, m) 3.02-3.19 (1H, m)3.26-3.37 (1H, m) 3.47 (1H, d, J=12.4 Hz) 3.57 (1H, dd, J=12.4, 0.8 Hz)3.93-4.05 (1H, m, J=12.3, 12.3, 1.3, 1.0 Hz) 4.07-4.18 (1H, m) 4.80 (1H,d) 5.23 (1H, s) 7.07 (1H, d) 7.33 (1H, d) 7.64 (1H, t) 7.68-7.74 (1H, m)7.77 (1H, d, J=7.6 Hz) 7.82 (1H, s).

Compound 50;3-{2-[4-(2,6-Dimethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 6H) 2.83-2.94 (m, 2H) 3.02-3.21(m, 2H) 3.26-3.40 (m, 3H) 3.41-3.51 (m, 1H) 3.51-3.61 (m, 1H) 3.91-4.06(m, 1H) 4.06-4.19 (m, 1H) 4.82 (dd, J=9.85, 1.01 Hz, 1H) 5.05 (s, 2H)6.74-6.81 (m, 0H) 7.04-7.11 (m, 2H) 7.17 (dd, J=8.34, 6.06 Hz, 2H)7.29-7.37 (m, 2H).

Compound 51;3-{2-[4-(3,5-Dichloro-pyridin-4-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.81-2.98 (m, 2H) 3.01-3.22 (m, 2H)3.24-3.42 (m, 2H) 3.42-3.70 (m, 2H) 3.92-4.19 (m, 2H) 4.85 (dd, J=11.17,1.13 Hz, 1H) 5.25 (s, 2H) 7.03-7.14 (m, 2H) 7.26-7.41 (m, 2H) 8.61-8.79(m, 2H)

Compound 52;3-{2-[4-(2,4-Dichloro-pyridin-3-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.83-2.98 (2H, m) 3.01-3.22 (2H, m)3.23-3.53 (3H, m) 3.52-3.65 (1H, m) 3.94-4.07 (1H, m) 4.08-4.21 (1H, m)4.84 (1H, dt, J=11.1, 0.7 Hz) 5.21-5.31 (2H, m) 7.04-7.18 (2H, m)7.29-7.44 (2H, m) 7.74 (1H, d, J=5.3 Hz) 8.45 (1H, d, J=5.3 Hz).

Compound 53;3-{2-[4-(2,6-Dichloro-phenylcarbamoyl)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85-2.98 (1H, m) 3.02-3.25 (1H, m) 3.35(1H, t, J=8.1 Hz) 3.51 (1H, d, J=12.6 Hz) 3.67-3.77 (1H, m) 4.07 (1H, t,J=12.4 Hz) 4.15-4.26 (1H, m) 4.96-5.07 (1H, m) 7.41 (1H, t, J=8.1 Hz)7.51-7.64 (2H, m) 8.06 (1H, d, J=8.3 Hz).

Compound 54;3-{2-[4-(2,6-Dichloro-phenoxymethyl)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.86-2.99 (2H, m) 3.00-3.25 (2H, m)3.24-3.42 (2H, m) 3.50 (1H, d, J=12.1 Hz) 3.65 (1H, d, J=12.6 Hz)4.00-4.12 (1H, m) 4.12-4.24 (1H, m) 4.89-4.99 (1H, m) 5.03 (2H, s) 7.22(1H, t, J=8.1 Hz) 7.36-7.49 (2H, m) 7.49-7.63 (3H, m).

Compound 55;3-(2-{4-[2-(2,6-Dichloro-phenyl)-vinyl]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85-2.95 (1H, m) 3.07 (1H, t, J=11.5Hz) 3.12-3.21 (1H, m) 3.35 (1H, t, J=7.8 Hz) 3.43-3.55 (1H, m) 3.60-3.70(1H, m) 3.97-4.07 (1H, m) 4.14-4.22 (1H, m) 4.90 (1H, dd, J=11.0, 0.6Hz) 7.07-7.14 (1H, m) 7.16-7.24 (1H, m) 7.34 (1H, t, J=8.1 Hz) 7.43 (1H,d, J=8.3 Hz) 7.55 (1H, d, J=8.1 Hz) 7.68 (1H, d, J=8.3 Hz).

Compound 56; 3-[2-(4-Phenethyl-phenyl)-morpholin-4-yl]-propionic acidhydro-chloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 2.80-3.23 (7H, m), 3.24-3.80 (4H, m),3.96-4.29 (2H, m), 4.80-5.04 (1H, m), 7.10-7.52 (9H, m).

Compound 57;3-{2-[4-(2,6-Dichloro-benzylamino)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.86-2.98 (2H, m) 3.01-3.18 (2H, m)3.26-3.36 (2H, m) 3.40-3.53 (2H, m) 3.94-4.05 (1H, m) 4.05-4.14 (1H, m)4.35-4.43 (2H, m) 4.72 (1H, dt, J=10.9, 1.1 Hz) 6.72 (2H, d, J=8.6 Hz)7.07-7.20 (2H, m) 7.12 (1H, d, J=8.8 Hz) 7.35-7.45 (1H, m) 7.51 (1H, d,J=7.8 Hz).

Compound 58;3-{2-[4-(2,6-Dichloro-benzoylamino)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.87-2.97 (2H, m) 2.99-3.22 (2H, m)3.27-3.42 (3H, m) 3.49 (1H, d, J=11.9 Hz) 3.60 (1H, dd, J=11.9, 1.0 Hz)3.98-4.10 (1H, m) 4.10-4.23 (1H, m) 4.88 (1H, dd, J=11.0, 0.6 Hz) 7.38(2H, d, J=8.6 Hz) 7.46-7.55 (1H, m) 7.55-7.63 (1H, m) 7.72 (1H, d, J=8.6Hz).

Compound 59;3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-2-methyl-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.84 (m, 3H) 2.95 (m, 2H) 3.02-3.42(m, 6H) 3.70-4.20 (m, 2H) 5.24 (s, 2H) 7.10 (d, J=7.6 Hz, 2H) 7.43-7.52(m, 3H) 7.56-7.60 (m, 2H) 11.41 (br. s., 1H) 12.85 (br. s., 1H).

Compound 60;3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-2-methyl-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.93 (m, 3H) 2.86-3.01 (m, 2H)3.02-3.44 (m, 6H) 3.60-4.20 (m, 2H) 5.16 (s, 2H) 7.09 (d, J=7.8 Hz, 2H)7.34 (t, J=8.8 Hz, 1H) 7.41-7.49 (m, 3H) 7.49-7.56 (m, 1H) 11.36 (br.s., 1H) 12.72 (br. s., 1H).

Compound 61;3-{2-[4-(2-Trifluoromethyl-benzyloxy)-phenyl]-2-methyl-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.90 (m, 3H) 2.86-3.00 (m, 2H)3.02-3.46 (m, 6H) 3.52-4.22 (m, 2H) 7.04 (d, J=7.3 Hz, 2H) 7.44 (d,J=8.6 Hz, 2H) 7.60 (t, J=7.3 Hz, 1H) 7.69-7.85 (m, 3H) 11.33 (m, 1H)12.71 (br. s., 1H).

Compound 62; 3-[2-Methyl-2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.92 (m, 3H) 1.20-1.89 (m, 13H)1.71 (quin, J=6.9 Hz, 2H) 2.85-2.99 (m, 2H) 3.00-3.43 (m, 6H) 3.53-4.16(m, 2H) 3.95 (t, J=6.4 Hz, 2H) 6.94 (d, J=8.7 Hz, 2H) 7.39 (d, J=8.7 Hz,2H) 11.23 (br. s., 1H) 12.72 (br. s., 1H).

Compound 63;4-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-butyric acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.92-2.04 (m, 2H) 2.35 (t, J=7.20 Hz,2H) 3.02-3.18 (m, 4H) 3.45-3.64 (m, 2H) 4.00-4.18 (m, 2H) 4.83-4.91 (m,1H) 5.23 (s, 2H) 7.07-7.13 (m, 2H) 7.32-7.38 (m, 2H) 7.45-7.51 (m, 1H)7.58 (d, J=7 Hz, 2H) 11.3 (br. s, 1H) 12.3 (br. s, 1H).

Compound 64;3-(2-{4-[1-(2,6-Dichloro-phenyl)-ethoxy]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.71 (d, J=6.6 Hz, 3H) 2.82-2.91 (m, 2H)2.96-3.13 (m, 2H) 3.21-3.35 (m, 2H) 3.39-3.56 (m, 2H) 3.96 (t, J=12.0Hz, 1H) 4.08 (d, J=11.1 Hz, 1H) 4.74 (d, J=10.6 Hz, 1H) 6.04 (q, J=6.6Hz, 1H) 6.84 (d, J=8.7 Hz, 2H) 7.24 (d, J=8.7 Hz, 2H) 7.31 (t, J=8.1 Hz,1H) 7.44 (d, J=8.1 Hz, 2H) 11.51 (br. s., 1H) 12.69 (br. s., 1H).

Compound 65;3-(2-{4-[2-(2,6-Dichloro-phenyl)-ethyl]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.76-2.83 (m, 2H) 2.85-2.93 (m, 2H)3.01-3.20 (m, 4H) 3.34 (t, J=8.02 H) 3.45-3.66 (m, 2H) 3.95-4.05 (m, 1H)4.16 (d, J=11.6 Hz 1H) 4.84 (d, J=10.1 Hz 1H) 7.27-7.36 (m, 5H) 7.48 (d,J=8.1 Hz, 2H) 11.31 (br. s., 1H) 12.67 (br. s., 1H).

Compound 66;3-{2-[3-Methoxy-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 170-172° C.

Compound 67;3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-3-methoxy-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 169-171° C.

Compound 68;3-{2-[4-(2,6-Dichloro-benzyloxy)-3-methoxy-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 214-216° C.

Compound 139:3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2-methyl-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.26 (m, 3H) 3.01-3.22 (m, 4H)3.41-3.63 (m, 3H) 3.97-4.08 (m, 1H) 4.09-4.16 (m, 1H) 4.81-4.90 (m, 1H)5.24 (s, 2H) 7.10 (d, J=8.6 Hz, 2H) 7.31-7.37 (m, 2H) 7.45-7.51 (m, 1H)7.57 (d, J=8.3 Hz, 2H) 10.2-10.9 (bs, 1H) 12.5-13.1 (bs, 1H).

Compound 140:3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-butyric acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (d, J=6.6 Hz, 3H) 2.54-2.64 (m, 1H)3.03-3.24 (m, 2H) 3.33-3.76 (m, 4H) 4.01-4.22 (m, 2H) 4.86-4.94 (m, 1H)5.23 (s, 2H) 7.10 (d, J=8.6 Hz, 2H) 7.38 (d, J=8.6 Hz, 2H) 7.45-7.51 (m,1H) 7.57 (d, J=8.3 Hz, 2H) 10.9-11.4 (bs, 1H) 12.5-13.0 (bs, 1H).

Compound 142: Phosphoric acidmono-(2-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethyl)esterhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.03-3.19 (m, 2H) 3.30-3.41 (m, 2H)3.43-3.51 (m, 1H) 3.52-3.65 (m, 1H) 3.94-4.05 (m, 1H) 4.09-4.24 (m, 3H)4.82 (d, J=10.6 Hz, 1H) 5.23 (s, 2H) 7.10 (d, J=8.6 Hz, 2H) 7.34 (d,J=8.6 Hz, 2H) 7.44-7.51 (m, 1H) 7.57 (d, J=8.3 Hz, 2H) 10.1-11.5 (bs,1H).

Compound 143:3-{2-[3-Methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]morpholin-4-yl}-propionicacid hydrochloride

Mp 191-194° C.

Compound 144:3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-3-methyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 194-196° C.

Compound 145:3-{2-[4-(2,6-Dichloro-benzyloxy)-3-methyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 198-200° C.

Compound 147:3-{2-[4-(2,3-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

Mp 222-227° C.

Compound 148:3-{2-[4-(2-Chloro-5-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 218.5-222° C.

Compound 152:3-{2-[4-(2-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 223-228° C.

Compound 153:3-{2-[4-(2-Chloro-6-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 185.5-190.5° C.

Compound 154:3-{2-[4-(2,3,6-Trichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 213-216° C.

Compound 155:3-{2-[4-(2-Chloro-6-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 215-218° C.

Compound 156:3-{2-[4-(2-Chloro-5-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 209-213° C.

Compound 157:3-{2-[4-(2-Chloro-5-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 198-202° C.

Compound 158:3-{2-[4-(2-Chloro-5-propyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 199-203° C.

Compound 159:3-{2-[4-(2-Chloro-5-isopropyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 203-207° C.

Compound 160:3-{2-[4-(2,4,6-Trichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 215-218° C.

Compound 161:3-{2-[4-(2,6-Dichloro-4-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 221-226° C.

Compound 162:3-{2-[4-(2,6-Dichloro-4-iodo-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 210-215° C.

Compound 163:3-(2-{4-[3-(2-Fluoro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.96-2.05 (m, 2H) 2.76-2.81 (m, 2H)2.83-2.96 (m, 2H) 3.04-3.17 (m, 2H) 3.28-3.37 (m, 2H) 3.47 (d, J=12.2Hz, 1H) 3.56 (d, J=12.2 Hz, 1H) 3.94-4.04 (m, 3H) 4.08-4.16 (m, 1H) 4.78(d, J=10.6 Hz 1H) 6.95 (J=8.6 Hz, 2H) 7.10-7.17 (m, 2H) 7.22-7.34 (m,4H) 11.0-11.6 (bs, 1H) 12.1-12.9 (bs, 1H).

Compound 164:3-{2-[4-(2,6-Dichloro-4-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 198-202° C.

Compound 165:3-{2-[4-(2,6-Dichloro-4-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 197-204° C.

Compound 166: 3-[2-(4-Benzyloxy-phenyl)-5-oxo-morpholin-4-yl]-propionicacid

¹H NMR (400 MHz, CDCl₃) δ ppm 2.71-2.79 (m, 2H) 3.41-3.49 (m, 1H)3.56-3.72 (m, 3H) 4.28-4.45 (m, 2H) 4.70-4.76 (m, 1H) 5.07 (s, 2H) 6.98(d, J=8.8 Hz, 2H) 7.27-7.45 (m, 7H).

Compound 167:3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-5-oxo-morpholin-4-yl}-propionicacid

¹H NMR (400 MHz, CDCl₃) δ ppm 2.67-2.83 (m, 2H) 3.43-3.51 (m, 1H)3.57-3.66 (m, 1H) 3.67-3.75 (m, 2H) 4.29-4.47 (m, 2H) 4.72-4.79 (m, 1H)5.27 (s, 2H) 7.03 (d, J=8.8 Hz, 2H) 7.22-7.29 (m, 1H) 7.30-7.40 (m, 4H)

Compound 168: 3-(2-(4-Octyloxy-phenyl)-5-oxo-morpholin-4-yl]-propionicacid

¹H NMR (400 MHz, CDCl₃) δ ppm 0.85-0.93 (m, 3H) 1.22-1.39 (m, 8H)1.39-1.50 (m, 2H) 1.72-1.82 (m, 2H) 2.67-2.81 (m, 2H) 3.41-3.48 (m, 1H)3.61 (t, J=12.3 Hz, 1H) 3.69 (t, J=6.6 Hz, 2H) 3.94 (t, J=6.6 Hz, 2H)4.27-4.45 (m, 2H) 4.69-4.74 (m, 1H) 6.89 (d, J=8.8 Hz, 2H) 7.28 (d,J=8.8 Hz, 2H).

Compound 169:3-(2-{4-[3-(2-Trifluoromethyl-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.97-2.07 (m, 2H) 2.84-2.95 (m, 4H)3.04-3.19 (m, 2H) 3.29-3.38 (m, 2H) 3.47 (d, J=11.9 Hz, 1H) 3.53-3.60(m, 1H) 3.94-4.08 (m, 3H) 4.09-4.17 (m, 1H) 4.80 (d, J=9.3 Hz, 1H) 6.96(d, J=8.7 Hz, 2H) 7.30 (d, J=8.7 Hz, 2H) 7.39-7.46 (m, 1H) 7.52 (d,J=7.8 Hz, 1H) 7.58-7.65 (m, 1H) 7.68 (d, J=7.8 Hz, 1H) 11.2 (bs, 1H)12.8 (bs, 1H).

Compound 170:3-(2-{4-[3-(2-Chloro-6-fluoro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.90-2.02 (m, 2H) 2.83-2.95 (m, 4H)3.04-3.18 (m, 2H) 3.33 (t, J=7.9 Hz, 2H) 3.47 (d, J=11.9 Hz, 1H) 3.57(d, J=11.9 Hz, 1H) 3.95-4.05 (m, 3H) 4.13 (d, J=11.9 Hz, 1H) 4.78 (d,J=10.0 Hz, 1H) 6.96 (J=8.6 Hz, 2H) 7.16-7.23 (m, 1H) 7.27-7.35 (m, 4H)10.9-11.4 (bs, 1H) 12.1-12.9 (bs, 1H).

Compound 171:3-(2-{4-[3-(2,6-Dichloro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.92-2.01 (m, 2H) 2.84-2.91 (m, 2H)3.01-3.16 (m, 3H) 3.28-3.38 (m, 2H) 3.47 (d, J=12.2 Hz, 2H) 3.58 (d,J=12.2 Hz, 1H) 3.93-4.01 (m, 1H) 4.03-4.08 (m, 2H) 4.13 (d, J=12.1 Hz,1H) 4.77 (d, J=10.4 Hz, 1H) 6.95 (d, J=8.9 Hz, 2H) 7.25-7.33 (m, 3H)7.46 (d, J=8.1 Hz, 2H) 10.8-11.4 (bs, 1H) 12.2-12.9 (bs, 1H).

Compound 172:3-(2-{4-[3-(4-Chloro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.95-2.05 (m, 2H) 2.69-2.76 (m, 2H)2.84-2.94 (m, 2H) 3.04-3.16 (m, 2H) 3.28-3.37 (m, 2H) 3.47 (d, J=12.3Hz, 1H) 3.56 (d, J=12.3, 1H) 3.92-4.04 (m, 3H) 4.15 (d, J=12.3 Hz, 1H)4.80 (d, J=9.6 Hz, 1H) 6.95 (d, J=8.7 Hz, 2H) 7.24-7.36 (m, 6H)10.9-11.9 (bs, 1H) 12.2-12.9 (bs, 1H).

Compound 173:3-(2-{4-[3-(2-Chloro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.97-2.09 (m, 2H) 2.83-2.95 (m, 4H)3.04-3.17 (m, 2H) 3.33 (t, J=7.9 Hz, 2H) 3.47 (d, J=12.1 Hz, 1H) 3.56(d, J=12.1 Hz, 1H) 3.96-4.05 (m, 3H) 4.13 (d, J=12.1 Hz, 1H) 4.79 (d,J=10.0 Hz, 1H) 6.96 (J=8.6 Hz, 2H) 7.20-7.31 (m, 4H) 7.33-7.37 (m, 1H)7.40-7.45 (m, 1H) 11.0-11.4 (bs, 1H) 12.1-12.9 (bs, 1H).

Compound 174:3-(2-{4-[3-(2,3-Difluoro-phenyl)-propoxy]-phenyl}-morpholin-4-yl)-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.98-2.08 (m, 2H) 2.82-2.88 (m, 2H)2.88-2.94 (m, 2H) 3.01-3.16 (m, 2H) 3.28-3.38 (m, 2H) 3.47 (d, J=12.2Hz, 1H) 3.58 (d, J=12.2 Hz, 1H) 3.93-4.08 (m, 3H) 4.13 (d, J=12.1 Hz,1H) 4.82 (d, J=10.4 Hz, 1H) 6.95 (d, J=8.9 Hz, 2H) 7.11-7.18 (m, 2H)7.22-7.32 (m, 3H) 11.2-11.9 (bs, 1H) 12.2-12.9 (bs, 1H).

Compound 175:3-{2-[3-Chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 179-181° C.

Compound 176:3-{2-[3-Chloro-4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 178-180° C.

Compound 177;3-{2-[3-Chloro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 199-201° C.

Compound 178;3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-2-fluoro-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 189-190° C.

Compound 179;3-{2-[4-(2,6-Dichloro-benzyloxy)-2-fluoro-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 174.5-178° C.

Compound 180;3-{2-[2-Fluoro-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 201-201.5° C.

Compound 181;3-{2-[4-(2,6-Dichloro-3-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (t, J=7.5 Hz, 3H) 2.75 (q, J=7.5Hz, 2H) 2.83-2.95 (m, 2H) 2.99-3.18 (m, 2H) 3.30-3.38 (m, 2H) 3.48 (d,J=12.7 Hz, 1H) 3.57-3.65 (m, 1H) 3.95-4.04 (m, 1H) 4.10-4.17 (m, 1H)4.81 (d, J=11.9 Hz, 1H) 5.26 (s, 2H) 7.11 (d, J=8.7 Hz, 2H) 7.34 (d,J=8.7 Hz, 2H) 7.46 (d, J=8.4 Hz, 1H) 7.52 (d, J=8.4 Hz, 1H) 10.9-11.9(bs, 1H) 12.2-12.9 (bs, 1H).

Compound 182;3-{2-[4-(2-Chloro-6-ethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (t, J=7.5 Hz, 3H) 2.72 (q, J=7.5Hz, 2H) 2.83-2.95 (m, 2H) 3.05-3.18 (m, 2H) 3.29-3.38 (m, 2H) 3.48 (d,J=11.9 Hz, 1H) 3.55-3.65 (m, 1H) 3.96-4.04 (m, 1H) 4.11-4.18 (m, 1H)4.82 (d, J=11.9 Hz, 1H) 5.17 (s, 2H) 7.10 (d, J=8.7 Hz, 2H) 7.27-7.39(m, 5H) 11.1-11.9 (bs, 1H) 12.2-12.9 (bs, 1H).

Compound 183;3-{2-[4-(2-Chloro-6-isopropyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (d, J=6.8 Hz, 6H) 2.84-2.96 (m, 2H)3.08-3.22 (m, 3H) 3.29-3.38 (m, 2H) 3.48 (d, J=12.8 Hz, 1H) 3.58 (d,J=12.8 Hz, 1H) 3.95-4.02 (m, 1H) 4.10-4.18 (m, 1H) 4.82 (d, J=10.1 Hz,1H) 5.21 (s, 2H) 7.10 (d, J=8.7 Hz, 2H) 7.31-7.44 (m, 5H) 11.0-11.8 (bs,1H) 12.2-12.9 (bs, 1H).

Compound 184;3-{2-[4-(2-Chloro-6-cyclopropyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.64-0.76 (m, 2H) 0.87-0.96 (m, 2H)2.02-2.11 (m, 1H) 2.85-2.97 (m, 2H) 3.06-3.18 (m, 2H) 3.32-3.41 (m, 2H)3.48 (d, J=12.4 Hz, 1H) 3.55-3.61 (m, 1H) 3.97-4.03 (m, 1H) 4.10-4.14(m, 1H) 4.83 (d, J=10.6 Hz, 1H) 5.33 (s, 2H) 7.10 dd, J=6.9 1.6 Hz, 1H)7.12 (d, J=8.8 Hz, 2H) 7.30-7.37 (m, 4H) 11.1-11.8 (bs, 1H) 12.4-13.0(bs, 1H).

Compound 185;3-{2-[4-(2-Chloro-6-isobutyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85 (d, J=6.6 Hz, 6H) 1.78-1.90 (m, 1H)2.58 (d, J=7.2 Hz, 2H) 2.84-2.92 (m, 2H) 3.06-3.18 (m, 2H) 3.32-3.41 (m,2H) 3.41-3.53 (m, 2H) 3.97-4.07 (m, 1H) 4.10-4.18 (m, 1H) 4.83 (d,J=10.5 Hz, 1H) 5.13 (s, 2H) 7.06 (d, J=8.8 Hz, 2H) 7.23 (dd, J=7.1, 1.8Hz, 1H) 7.30-7.41 (m, 4H) 11.1-11.8 (bs, 1H) 12.4-12.9 (bs, 1H).

Compound 186;3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-5,5-dimethyl-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.47 (m, 6H) 2.91-3.03 (m, 3H)3.12-3.23 (m, 1H) 3.51-3.64 (m, 2H) 3.79-3.88 (m, 1H) 3.92-4.01 (m, 1H)4.93 (d, J=11.9 Hz, 1H) 5.24 (s, 2H) 7.11 (d, J=8.8 Hz, 2H) 7.38 (d,J=8.8 Hz, 2H) 7.45-7.52 (m, 1H) 7.58 (d, J=7.8 Hz, 2H) 10.9-11.3 (bs,1H) 12.6-13.1 (bs, 1H).

Compound 187;3-[5,5-Dimethyl-2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-0.89 (m, 3H) 1.17-1.47 (m, 16H)1.63-1.75 (m, 2H) 2.91-3.04 (m, 3H) 3.12-3.23 (m, 1H) 3.47-3.64 (m, 2H)3.74-3.84 (m, 1H) 3.91-4.03 (m, 3H) 4.93 (d, J=11.9 Hz, 1H) 6.95 (d,J=8.8 Hz, 2H) 7.33 (d, J=8.8 Hz, 2H) 11.1 (bs, 1H) 12.8 (bs, 1H).

Compound 188;3-{2-[4-(2,6-Dichloro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 195-197° C.

Compound 189;3-[2-(4-Octyloxy-2-trifluoromethyl-phenyl)-morpholin-4-yl]-propionicacid hydrochloride

Mp 178.5-180.5° C.

Compound 190;3-{6-[4-(2,6-Dichloro-benzyloxy)-phenyl]-2,2-dimethyl-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 3H) 1.53 (s, 3H) 2.85-2.97 (m,4H) 3.29-3.35 (m, 2H) 3.46-3.53 (m, 2H) 4.93 (d, J=11.9 Hz, 1H) 5.24 (s,2H) 7.10 (d, J=8.8 Hz, 2H) 7.33 (d, J=8.8 Hz, 2H) 7.44-7.52 (m, 1H) 7.57(d, J=7.8 Hz, 2H) 10.5-10.9 (bs, 1H) 12.5-13.0 (bs, 1H).

Compound 191;3-[2,2-Dimethyl-6-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86 (t, J=6.8 Hz, 3H) 1.19-1.45 (m,13H) 1.54 (s, 3H) 1.64-1.75 (m, 2H) 2.84-3.02 (m, 4H) 3.24-3.36 (m, 2H)3.39-3.51 (m, 2H) 3.95 (t, J=6.5 Hz, 2H) 4.92 (d, J=10.6 Hz, 1H) 6.94(d, J=8.5 Hz, 2H) 7.27 (d, J=8.5 Hz, 2H) 10.9-11.4 (bs, 1H) 12.5-13.0(bs, 1H).

Compound 192;3-{2-[4-(2,6-Dichloro-4-propyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 101-103° C.

Compound 193;3-{2-[4-(2,6-Dichloro-4-isopropyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 108-110° C.

Compound 194;3-{2-[4-(2,6-Dichloro-4-prop-1-ynyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 220-224° C.

Compound 195;3-{2-[4-(2-Chloro-6-trifluoromethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85-2.97 (m, 2H) 3.06-3.18 (m, 2H)3.29-3.38 (m, 1H) 3.48 (d, J=11.9 Hz, 1H) 3.59 (d, J=11.9, 1H) 3.95-4.07(m, 1H) 4.09-4.18 (m, 1H) 4.83 (d, J=10.6 Hz, 1H) 5.16 (s, 2H) 7.09 (d,J=8.8 Hz, 2H) 7.35 (d, J=8.8 Hz, 2H) 7.48-7.52 (m, 2H) 7.58-7.68 (m, 2H)11.2-11.9 (bs, 1H) 12.4-13.0 (bs, 1H).

Compound 196;3-{2-[4-(2-Chloro-4-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H) 2.83-2.92 (m, 2H) 3.04-3.17(m, 2H) 3.28-3.40 (m, 2H) 3.47 (d, J=10.6 Hz, 1H) 3.57 (d, J=10.6 Hz,1H) 3.94-4.05 (m, 1H) 4.08-4.16 (m, 1H) 4.83 (d, J=10.2 Hz, 1H) 5.12 (s,2H) 7.04 (d, J=8.8 Hz, 2H) 7.18 (d, J=7.8 Hz, 1H) 7.27-7.39 (m, 3H) 7.46(d, J=7.8 Hz, 1H) 11.2-12.0 (bs, 1H) 12.3-13.0 (bs, 1H).

Compound 197;3-{2-[4-(2-Chloro-3-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.38 (s, 3H) 2.81-2.89 (m, 2H) 3.04-3.18(m, 2H) 3.30-3.52 (m, 3H) 3.55-3.61 (m, 1H) 3.92-4.02 (m, 1H) 4.13 (d,J=12.6 Hz, 1H) 4.78 (d, J=10.2 Hz, 1H) 5.17 (s, 2H) 7.06 (d, J=8.8 Hz,2H) 7.27-7.43 (m, 5H) 10.8-11.5 (bs, 1H) 12.3-13.0 (bs, 1H).

Compound 198;3-{2-[4-(2,4-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.85-2.97 (m, 2H) 3.04-3.17 (m, 2H)3.28-3.38 (m, 2H) 3.42-3.51 (m, 1H) 3.52-3.62 (m, 1H) 3.96-4.06 (m, 1H)4.09-4.17 (m, 1H) 4.83 (d, J=10.4 Hz, 1H) 5.16 (s, 2H) 7.06 (d, J=8.8Hz, 2H) 7.32 (d, J=8.8 Hz, 2H) 7.49 (dd, J=8.3, 2.1 Hz, 1H) 7.61 (d,J=8.3 Hz, 1H) 7.70 (d, J=2.1 Hz, 1H) 11.2-12.0 (bs, 1H) 12.3-12.9 (bs,1H).

Compound 199; 2,6-Dichloro-benzoic acid4-[4-(2-carboxy-ethyl)-morpholin-2-yl]-phenyl ester hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.89-2.96 (m, 2H) 3.09-3.22 (m, 2H)3.30-3.41 (m, 2H) 3.51 (d, J=12.0 Hz, 1H) 3.70 (d, J=12.0 Hz, 1H)4.01-4.11 (m, 1H) 4.15-4.23 (m, 1H) 4.96 (d, J=10.5 Hz, 1H) 7.36 (d,J=8.7 Hz, 2H) 7.55 (d, J=8.7 Hz, 2H) 7.61-7.73 (m, 3H)) 11.2-11.9 (bs,1H) 12.1-12.7 (bs, 1H).

Compound 200;3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-cyclo-butanecarboxylicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.40-2.53 (m, 2H) 2.81-3.00 (m, H)3.32-3.50 (m, 4H) 3.54-3.66 (m, 1H) 3.89-4.01 (m, 1H) 4.10-4.20 (m, 1H)4.75 (d, J=10.8 Hz, 1H) 5.20 (s, 2H) 7.10 (d, J=8.8 Hz, 2H) 7.37 (d,J=8.8 Hz, 2H) 7.45-7.50 (m, 1H) 7.55-7.59 (m, 2H) 11.1 (bs, 1H) 12.6(bs, 1H).

Compound 201;3-{2-[4-(2,6-Dichloro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84-2.96 (m, 2H) 3.05-3.09 (m, 1H)3.11-3.18 (m, 1H) 3.33 (t, J=7.9 Hz, 1H) 3.49 (d, J=11.0 Hz, 1H) 3.64(d, J=11.0 Hz, 1H) 3.97-4.06 (m, 1H) 4.12-4.20 (m, 1H) 4.41 (s, 2H) 4.87(1H) 4.86 (d, J=10.4 Hz, 1H) 7.31-7.39 (m, 3H) 7.42-7.52 (m, 4H)11.0-12.0 (bs, 1H) 12.3-13.0 (bs, 1H).

Compound 202;3-{2-[4-(2-Chloro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84-2.96 (m, 2H) 3.00-3.18 (m, 2H)3.28-3.37 (m, 2H) 3.47 (d, J=12.0 Hz, 1H) 3.61 (d, J=12.0 Hz, 1H)3.96-4.07 (m, 1H) 4.10-4.18 (m, 1H) 4.32 (s, 2H) 4.86 (d, J=11.4 Hz, 1H)7.23-7.35 (m, 4H) 7.37-7.43 (m, 3H) 7.43-7.48 (m, 1H) 11.2-11.9 (bs, 1H)12.3-12.9 (bs, 1H).

Compound 203;3-{2-[4-(2-Chloro-6-fluoro-benzylsulfanyl)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84-2.91 (m, 2H) 3.01-3.18 (m, 2H)3.30-3.38 (m, 2H) 3.48 (d, J=12.0 Hz, 1H) 3.63 (d, J=12.0 Hz, 1H)3.93-4.05 (m, 1H) 4.12-4.19 (m, 1H) 4.29 (s, 2H) 4.80-4.88 (m, 1H)7.17-7.24 (m, 1H) 7.32-7.45 (m, 6H)) 11.0-11.6 (bs, 1H) 12.1-12.7 (bs,1H).

Compound 204; 3-[2-(4-Octylsulfanyl-phenyl)-morpholin-4-yl]-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-0.89 (m, 3H) 1.19-1.31 (m, 8H)1.32-1.43 (m, 2H) 1.51-1.61 (m, 2H) 2.86-2.92 (m, 2H) 2.94-2.99 (m, 2H)3.01-3.18 (m, 2H) 3.27-3.37 (m, 2H) 3.46 (d, J=12.1 Hz, 1H) 3.60 (d,J=12.1 Hz, 1H) 3.96-4.06 (m, 1H) 4.10-4.18 (m, 1H) 4.84 (d, J=10.4 Hz,1H) 7.28-7.36 (m, 4H) 11.0-12.9 (bs, 2H).

Compound 205;3-{2-[4-(4,4-Dimethyl-cyclohexyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (d, J=3.3 Hz, 6H) 1.22-1.32 (m.,2H) 1.39-1.47 (m., 2H) 1.50-1.61 (m., 2H) 1.75-1.84 (m., 2H) 2.82-2.90(m, 2H) 3.02-3.16 (m, 2H) 3.26-3.59 (m, 4H) 3.94 (t, J=11.4, 1H) 4.12(d, J=11.4 Hz, 1H) 4.30-4.39 (m, 1H) 4.73 (d, J=11.4 Hz, 1H) 6.95 (d,J=8.7 Hz, 2H) 7.27 (d, J=8.7 Hz, 2H) 10.9 (bs, 1H) 12.9 (bs, 1H).

Compound 206;3-{2-[4-(2-Difluoromethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84-2.92 (m, 2H) 3.04-3.16 (m, 2H)3.28-3.38 (m, 2H) 3.43-3.51 (m, 1H) 3.53-3.61 (m, 1H) 3.97 (t, J=11.4,1H) 4.13 (dd, J=11.4, 2.4 Hz, 1H) 4.78 (d, J=11.4 Hz, 1H) 5.12 (s, 2H)7.02-7.09 (m, 2H) 7.25 (t, J=75 Hz, 1H) 7.24-7.35 (m, 4H) 7.42-7.48 (m,1H) 7.57 (dd, J=7.6, 1.9 Hz, 1H) 11.1 (bs, 1H) 12.9 (bs, 1H).

Compound 207;3-{2-[4-(3-Trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 209-211° C.

Compound 208;3-{2-[4-(2-Chloro-6-ethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 214-215° C.

Compound 209;3-{2-[4-(2-Chloro-6-trifluoromethoxy-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 179-182° C.

Compound 210;3-{2-[4-(2-Chloro-6-isopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 206-210° C.

Compound 211;3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 171.5-172.5° C.

Compound 212;3-{2-[4-(2-Chloro-6-trifluoromethyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 200-201° C.

Compound 213;3-{2-[4-(2-Chloro-6-cyclopropyl-benzyloxy)-2-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 203-204° C.

Compound 214;3-{2-[4-(2,6-Diethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (t, J=7.5 Hz, 6H) 1.88 (d, J=11.3Hz, 1H) 2.01-2.10 (m., 3H) 2.45-2.55 (m., 2H) 2.66 (q, J=7.4 Hz, 4H)2.71-2.75 (m., 1H) 2.80-2.85 (m., 1H) 3.58-3.67 (m., 1H) 3.87-3.92 (m.,1H) 4.37-4.42 (m., 1H) 5.01 (s, 2H) 7.01 (d, J=8.7 Hz, 2H) 7.11 (d,J=7.8 Hz, 2H) 7.23-7.31 (m, 3H).

Compound 215;3-{2-[2-Chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.87-2.93 (m, 2H) 3.04-3.20 (m, 2H)3.30-3.38 (m, 2H) 3.46-3.55 (m, 2H) 4.02-4.11 (m, 1H) 4.12-4.20 (m, 1H)5.19-5.25 (m, 1H) 5.27 (s, 2H) 7.15 (dd, J=8.8, 2.6 Hz, 1H) 7.28 (d,J=2.6 Hz, 1H) 7.46-7.53 (m, 2H) 7.59 (d, J=8.8 Hz, 2H) 11.8-12.9 (bs,2H).

Compound 216:3-{2-[4-(2,6-Dichloro-benzyl)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.83-2.93 (m, 2H) 2.97-3.20 (m, 2H)3.22-3.39 (m, 2H) 3.47 (d, J=12.38 Hz, 1H) 3.55-3.66 (m, 1H) 3.94-4.06(m, 1H) 4.08-4.19 (m, 1H) 4.28 (s, 2H) 4.78-4.89 (m, 1H) 7.15 (d, J=8.34Hz, 2H) 7.26-7.40 (m, 3H) 7.53 (d, J=8.08 Hz, 2H).

Compound 217:3-{2-[4-(2-Chloro-6-difluoromethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.88-2.95 (m, 2H) 3.05-3.18 (m, 2H)3.28-3.39 (m, 2H) 3.42-3.51 (m, 1H) 3.53-3.62 (m, 1H) 3.97 (t, J=11.4,1H) 4.13 (d, J=11.4 Hz, 1H) 4.84 (d, J=11.4 Hz, 1H) 5.13 (s, 2H) 7.08(d, J=8.7 Hz 2H) 7.33 (t, J=85 Hz, 1H) 7.26-7.37 (m, 3H) 7.47 (d, J=7.6Hz, 1H) 7.56 (d, J=7.6, 1.9 Hz, 1H) 11.8 (bs, 1H) 12.8 (bs, 1H).

Compound 218:3-{2-[4-(2-Chloro-6-difluoromethoxy-benzyloxy)-2-trifluoro-methyl-phenyl]-morpholin-4-yl}-propionicacid hydrochloride

Mp 192-193° C.

Compound 230; 3-[2-(3-Benzyloxy-phenyl)-morpholin-4-yl]-propionic acidhydrochloride

Mp 222-225° C.

Compound 231; 3-[2-(3-Octyloxy-phenyl)-morpholin-4-yl]-propionic acidhydrochloride

Mp 218-220° C.

Compound 232;3-{2-[3-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

Mp 229-230° C.

Compound 233;3-{2-[3-(2-Chloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

Mp 233-234° C.

Compound 234; 3-[2-(4-Benzyloxy-phenyl)-thiomorpholin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91-1.99 (m, 2H) 2.11-2.19 (m, 1H)2.25-2.33 (m, 1H) 2.47-2.54 (m, 3H) 2.72-2.83 (m, 1H) 2.91-3.04 (m, 2H)3.81-3.88 (m, 1H) 5.01 (s, 2H) 6.88 (d, J=8.8 Hz, 2H) 7.18-7.39 (m, 7H).

Compound 235;3-{2-[4-(2-Chloro-benzyloxy)-phenyl]-thiomorpholin-4-yl}-propionic acidhydrochloride

Mp 178-182° C.

Compound 236;3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]thiomorpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.89-2.99 (m, 3H) 3.10-3.20 (m, 1H)3.33-3.54 (m, 4H) 3.71-3.83 (m, 2H) 4.54-4.60 (m, 1H) 5.23 (s, 2H) 7.11(d, J=8.7 Hz, 2H) 7.32 (d, J=8.7 Hz, 2H) 7.46-7.52 (m, 1H) 7.55-7.59 (m,2H) 11.4 (bs, 1H) 12.8 (bs, 1H).

Compound 237; 3-[2-(4-Octyloxy-phenyl)-thiomorpholin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-0.90 (m, 3H) 1.23-1.34 (m, 8H)1.35-1.42 (m, 2H) 1.64-1.73 (m, 2H) 2.26-2.34 (m, 1H) 2.35-2.41 (m, 2H)2.41-2.48 (m, 1H) 2.57-2.63 (m, 1H) 2.64-2.70 (m, 2H) 2.81-2.89 (m, 1H)3.02-3.14 (m, 2H) 3.89-3.96 (m, 3H) 6.86 (d, J=8.8 Hz, 2H) 7.26 (d,J=8.8 Hz, 2H).

Compound 238;3-{2-[5-(2,6-Dichloro-benzyloxy)-pyridin-2-yl]-morpholin-4-yl}-propionicacid hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.88-2.97 (m, 2H) 3.11-3.26 (m, 2H)3.32-3.44 (m, 2H) 3.52 (d, J=11.9 Hz, 1H) 3.74 (d, J=11.9 Hz, 1H)4.06-4.21 (m, 2H) 5.01 (d, J=11.9 Hz, 1H) 5.34 (s, 2H) 7.38 (bs, 1H)7.47-7.55 (m, 2H) 7.56-7.61 (m, 2H) 7.69 (dd, J=8.7, 3.0 Hz, 1H) 8.40(d, J=3.0 Hz, 1H) 11.8 (bs, 1H).

Compound 239;3-{2-[4-(2-Oxo-2-phenyl-ethyl)-phenyl]-morpholin-4-yl}-propionic acidhydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84-2.92 (m, 2H) 3.00-3.18 (m, 2H)3.28-3.38 (m, 2H) 3.42-3.51 (m, 1H) 3.58-3.66 (m, 1H) 3.94-4.04 (m, 1H))4.11-4.19 (m, 1H) 4.42 (s, 2H) 4.79-4.87 (m, 1H) 7.28-7.37 (m., 4H) 7.54(t, J=7.6 Hz, 2H) 7.65 (t, J=7.0 Hz, 1H) 8.05 (t, J=7.6 Hz, 2H) 11.2(bs, 1H) 12.8 (bs, 1H)

Method C Compound 69;3-{2-[4-(3-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

3-{2-[4-(3-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester was dissolved in a 4M solution of HCl in1,4-dioxane (1 mL, 4 mmol) and stirred overnight at RT. Subsequently,the solvent was removed in vacuo. The residue was purified bypreparative HPLC to afford3-{2-[4-(3-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid R_(t)=1.00 min. (System B). Conditions for the preparative LC-MS:Injection of the crude product dissolved in 2700 μL DMSO/CH₃CN 1:2;column Waters SunFire Prep OBD C18 Column 5 μm 30×100 mm, mobile phasewater/CH₃CN/HCOOH 0.1% 40 mL/min, run 8.5 min 5%-100% CH₃CN, detectionwith UV 225 nm.

The following compounds were obtained according to a similar manner:

Compound 70;3-{2-[4-(5-Bromo-2-methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.26 min. (System B).

Compound 71;3-{2-[4-(2,4-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.61 min. (System B).

Compound 72;3-{2-[4-(2,3-Dimethoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.99 min. (System B).

Compound 73;3-[2-(4-Cyclopentylmethoxy-2-methyl-phenyl)-morpholin-4-yl]-propionicacid

R_(t)=1.05 min. (System B).

Compound 74;3-{2-[4-(2,5-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.10 min. (System B).

Compound 75;3-{2-[2-Methyl-4-(pyridin-3-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.68 min. (System B).

Compound 76;3-{2-[2-Methyl-4-(naphthalen-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.10 min. (System B).

Compound 77;3-{2-[4-(Benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionic acid

R_(t)=1.01 min. (System B).

Compound 78;3-{2-[4-(2-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.92 min. (System B).

Compound 79;3-{2-[2-Methyl-4-(6-methyl-pyridin-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.71 min. (System B).

Compound 80;3-{2-[4-(2-Chloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.04 min. (System B).

Compound 81;3-{2-[4-(2,5-Dimethoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.93 min. (System B).

Compound 82;3-{2-[4-(2-Bromo-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.05 min. (System B).

Compound 83;3-{2-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.04 min. (System B).

Compound 84;3-{2-[4-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-ylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.21 min. (System B).

Compound 85;3-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.03 min. (System B).

Compound 86;3-{2-[4-(Biphenyl-2-ylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.13 min. (System B).

Compound 87;3-{2-[2-Methyl-4-(2-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.06 min. (System B).

Compound 88;3-{2-[4-(3,5-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.13 min. (System B).

Compound 89;3-{2-[2-Methyl-4-(3-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.09 min. (System B).

Compound 90;3-{2-[4-(4-Chloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.06 min. (System B).

Compound 91;3-{2-[4-(4-Isopropyl-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.14 min. (System B).

Compound 92;3-{2-[2-Methyl-4-(3-phenoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.15 min. (System B).

Compound 93;3-{2-[4-(4-Methoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.92 min. (System B).

Compound 94;3-{2-[2-Methyl-4-(2-phenethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.19 min. (System B).

Compound 95;3-{2-[4-(3,4-Dimethoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.86 min. (System B).

Compound 96;3-{2-[4-(3,5-Dimethyl-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.08 min. (System B).

Compound 97;3-{2-[4-(4-Benzyloxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.05 min. (System B).

Compound 98;3-{2-[2-Methyl-4-(thiophen-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.90 min. (System B).

Compound 99;3-{2-[4-(3-Fluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.03 min. (System B).

Compound 100;3-{2-[4-(3-Benzyloxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.15 min. (System B).

Compound 101;3-{2-[4-(4-Fluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.01 min. (System B).

Compound 102;3-{2-[4-(Biphenyl-4-ylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.14 min. (System B).

Compound 103;3-{2-[4-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.03 min. (System B).

Compound 104;3-{2-[2-Methyl-4-(pyridin-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.75 min. (System B).

Compound 105;3-{2-[4-(4-Butoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.05 min. (System B).

Compound 106;342-(4-Cyclohexylmethoxy-2-methyl-phenyl)-morpholin-4-yl]-propionic acid

R_(t)=1.10 min. (System B).

Compound 107;3-{2-[2-Methyl-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.83 min. (System B).

Compound 108;3-{2-[2-Methyl-4-(3-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.05 min. (System B).

Compound 109;3-{2-[4-(2,3-Difluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.03 min. (System B).

Compound 110;3-{2-[2-Methyl-4-(4-trifluoromethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.12 min. (System B).

Compound 111;3-{2-[4-(3-Chloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.05 min. (System B).

Compound 112;3-{2-[2-Methyl-4-(tetrahydro-pyran-2-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.91 min. (System B).

Compound 113;3-{2-[2-Methyl-4-(4-trifluoromethyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.08 min. (System B).

Compound 114;3-{2-[4-(3,4-Difluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.05 min. (System B).

Compound 115;3-{2-[2-Methyl-4-(2,3,4-trimethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.91 min. (System B).

Compound 116;3-{2-[4-(Cyclohex-3-enylmethoxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.07 min. (System B).

Compound 117;3-{2-[4-(4-Butyl-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.22 min. (System B).

Compound 118;3-{2-[2-Methyl-4-(4-methyl-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.05 min. (System B).

Compound 119;3-{2-[4-(3-Dimethylamino-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.86 min. (System B).

Compound 120;3-{2-[2-Methyl-4-(pyridin-4-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.66 min. (System B).

Compound 121;3-{2-[4-(2-Iodo-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.07 min. (System B).

Compound 122;3-{2-[4-(3,5-Dimethoxy-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.00 min. (System B).

Compound 123;3-{2-[4-(2,4-Difluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.03 min. (System B).

Compound 124;3-{2-[2-Methyl-4-(2,4,5-trimethoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.88 min. (System B).

Compound 125;3-{2-[4-(3-Bromo-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.08 min. (System B).

Compound 126;3-{2-[4-(4-Bromo-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.07 min. (System B).

Compound 127;3-{2-[4-(4-tert-Butyl-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.18 min. (System B).

Compound 128;3-{2-[4-(2,5-Difluoro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=1.02 min. (System B).

Compound 129;3-{2-[2-Methyl-4-(tetrahydro-furan-3-ylmethoxy)-phenyl]-morpholin-4-yl}-propionicacid

R_(t)=0.83 min. (System B).

Method D Compound 130;3-{2-[4-(2,6-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

3-{2-[4-(2,6-Dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid tert-butyl ester (1.23 g; 2.6 mmol) was dissolved in CH₂Cl₂ (15mL). TFA (5 mL) was added and the resulting mixture was stirredovernight at RT. The reaction mixture was concentrated in vacuo, and theresidue was treated with iPr₂O. The precipitate was collected byfiltration to afford3-{2-[4-(2,6-dichloro-benzyloxy)-2-methyl-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.27-2.38 (2H, m), 2.83 (2H, t, J=7.6 Hz), 3.07 (1H, t, J=11.7 Hz),3.13-3.28 (1H, m), 3.39 (2H, t, J=7.7 Hz), 3.48-3.69 (2H, m), 3.83-3.98(1H, m), 4.18 (1H, d), 4.90 (1H, d, J=10.6 Hz), 5.22 (2H, d), 6.88-7.01(2H, m), 7.34 (1H, d, J=8.3 Hz), 7.43-7.52 (1H, m), 7.58 (2H, d).

The following compound was obtained according to a similar manner:

Compound 131;3-{2-[4-(2,6-Dichloro-benzyloxy)-3-trifluoromethyl-phenyl]-morpholin-4-yl}-propionicacid trifluoroacetic acid salt

¹H NMR (400 MHz, DMSO-d₆) 8 ppm 2.73-2.90 (m, 2H) 3.07-3.26 (m, 2H)3.28-3.45 (m, 2H) 3.51 (d, J=12.1 Hz, 1H) 3.71 (d, J=12.1 Hz, 1H) 3.90(t, J=12.1 Hz, 1H) 4.20 (d, J=10.7 Hz, 1H) 4.81 (d, J=10.7 Hz, 1H) 5.38(s, 2H) 7.47-7.53 (m, 1H) 7.56-7.63 (m, 3H) 7.65-7.75 (m, 2H) 10.84 (br.s., 1H) 12.42 (br. s., 1H).

Method E Compound 132;{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-acetic acid

A mixture of{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-acetic acid ethylester (0.62 g; 1.5 mmol), 2M aqueous NaOH (5 mL) and ethanol (25 mL) wasstirred for 3 hours at RT. Subsequently, 1M aqueous HCl (9.8 mL) wasadded and the mixture concentrated in vacuo. The residue was treatedwith saturated NH₄CI and CH₂Cl₂. The formed precipitate was collected byfiltration, washed with small amounts of water and ethanol, and dried invacuo to yield{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-acetic acid (0.41g). ¹H NMR (400 MHz, DMSO-d₆) 8 ppm 2.23 (t, J=10 Hz, 1H) 2.40 (dt, J=10Hz J=3 Hz, 1H) 2.76-2.83 (m, 1H) 2.86-2.93 (m, 1H) 3.13-3.25 (m, 2H)3.67 (dt, J=11 Hz J=2 Hz, 1H) 3.87-3.95 (m, 1H) 4.46 (dd, J=10 Hz J=2Hz, 1H) 5.21 (s, 2H) 6.99-7.06 (m, 2H) 7.26-7.32 (m, 2H) 7.44-7.50 (m,1H) 7.57 (d, J=7 Hz, 2H) 12.3 (br. s, 1H).

The following compounds were obtained according to a similar manner:

Compound 219; 3-{2-[4-(Indan-1-yloxy)-phenyl]-morpholin-4-yl}propionicacid

Mp 124-129.5° C.

Compound 220;3-{2-[4-(7-Methyl-indan-1-yloxy)-phenyl]-morpholin-4-yl}-propionic acid

Mp 134-139° C.

Compound 221;3-{2-[4-(2,3-Dihydro-benzofuran-3-yloxy)-phenyl]-morpholin-4-yl}-propionicacid

Mp 141.5-144.5° C.

Compound 222;3-(2-{4-[3-(4-Chloro-phenyl)-allyloxy]-phenyl}-morpholin-4-yl)-propionicacid

¹H NMR (400 MHz, CDCl₃) δ ppm 2.33 (t, J=11.7 Hz, 1H) 2.47-2.59 (m, 3H)2.74-2.86 (m, 2H) 2.98-3.10 (m, 2H) 3.87 (td, J=11.9, 2.4 Hz, 1H) 4.13(dd, J=11.9, 2.4 Hz, 1H) 4.55 (dd, J=10.5, 2.5 Hz, 1H) 4.69 (dd, J=5.7,1.6 Hz, 2H) 6.32-6.42 (m, 1H) 6.68 (d, J=16.0 1H) 6.95 (d, J=8.8 Hz, 2H)7.23-7.36 (m, 6H).

Compound 223;3-{2-[4-(3-Phenyl-prop-2-ynyloxy)-phenyl]-morpholin-4-yl}-propionic acid

¹H NMR (400 MHz, CDCl₃) δ ppm 2.33 (t, J=11.7 Hz, 1H) 2.47-2.60 (m, 3H)2.74-2.86 (m, 2H) 2.98-3.11 (m, 2H) 3.87 (td, J=11.9, 2.5 Hz, 1H) 4.13(dd, J=11.9, 2.4 Hz, 1H) 4.55 (dd, J=10.5, 2.5 Hz, 1H) 4.91 (s, 2H) 7.03(d, J=8.8 Hz, 2H) 7.25-7.36 (m, 5H) 7.40-7.46 (m, 2H).

Compound 224;3-(2-{4-[3-phenyl-allyloxy]-phenyl}-morpholin-4-yl)-propionic acid

¹H NMR (400 MHz, CDCl₃) δ ppm 2.32 (t, J=11.7 Hz, 1H) 2.47-2.59 (m, 3H)2.75-2.87 (m, 2H) 2.98-3.11 (m, 2H) 3.87 (td, J=11.9, 2.5 Hz, 1H) 4.14(dd, J=10.5, 2.4 Hz, 1H) 4.55 (dd, J=10.5, 2.4 Hz, 1H) 4.70 (dd, J=5.7,1.6 Hz, 2H) 6.36-6.44 (m, 1H) 6.69 (d, J=15.9 1H) 6.95 (d, J=8.8 Hz, 2H)7.22-7.43 (m, 7H).

Compound 225;3-(2-{4-[3-(4-Chloro-phenyl)-prop-2-ynyloxy]-phenyl}-morpholin-4-yl)-propionicacid

¹H NMR (400 MHz, CDCl₃) δ ppm 2.28-2.36 (m, 1H) 2.47-2.59 (m, 3H)2.73-2.86 (m, 2H) 3.01 (d, J=11.5 Hz, 1H) 3.08 (d, J=11.5 Hz, 1H)3.86-3.91 (m, 1H) 4.11-4.16 (m, 1H) 4.53-4.58 (m, 1H) 4.89 (s, 2H) 7.03(d, J=8.7 Hz, 2H) 7.25-7.37 (m, 6H).

Compound 226;3-{2-[4-(4-Methoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.03-2.12 (m, 1H) 2.20-2.28 (m, 1H)2.41-2.48 (m, 2H) 2.63-2.71 (m, 2H) 2.82-2.87 (m, 1H) 2.88-2.96 (m, 1H)3.58-3.71 (m, 1H) 3.75 (s, 3H) 3.89-3.96 (m, 1H) 4.35-4.44 (m, 1H) 5.00(s, 2H) 6.88-6.99 (m, 4H) 7.25 (d, J=8.7 Hz, 2H) 7.37 (d, J=8.7 Hz, 2H)12.3 (bs, 1H).

Compound 227;3-{2-[4-(2-Methoxy-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.90-1.98 (m, 1H) 2.08-2.17 (m, 1H)2.36-2.44 (m, 2H) 2.54-2.61 (m, 2H) 2.73-2.79 (m, 1H) 2.82-2.88 (m, 1H)3.55-3.65 (m, 1H) 3.82 (s, 3H) 3.87-3.93 (m, 1H) 4.35-4.40 (m, 1H) 5.03(s, 2H) 6.91-6.99 (m, 3H) 7.05 (d, J=7.8 Hz, 1H) 7.27 (d, J=8.7 Hz, 2H)7.30-7.40 (m, 2H) 12.1-12.6 (bs, 1H).

Method F Compound 133;3-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-3-oxo-propionic acid

To a solution of3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-3-oxo-propionic acid ethylester (0.46 g; 1.1 mmol) in tetrahydrofuran (4 mL) and water (1 mL) wasadded lithium hydroxide (54.3 mg; 2.3 mmol) and the mixture was stirredat 70° C. for 3 hours. After cooling to RT the resulting mixture wasloaded onto a PE-AX column [ISOLUTE (Biotage AB); 0.58 mmol/g, 10 g].The column was washed with CH₃CN and than the required compound waseluted with 20 v/v % TFA in CH₃CN. The compound containing fractionswere concentrated in vacuo to afford3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-3-oxo-propionic acid (0.40 g)¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.83-0.89 (m, 3H) 1.22-1.34 (m, 8H) 1.39(d, J=7.52 Hz, 2H) 1.65-1.73 (m, 2H) 3.75 (d, J=1.20 Hz, 1H) 3.91-3.99(m, 3H) 4.27 (br. s., 1H) 6.89 (dd, J=8.58, 3.16 Hz, 2H) 7.28 (dd,J=8.43, 3.91 Hz, 2H)

Compound 151:3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-3-oxo-propionicacid

was obtained according to a similar manner. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 2.71-2.79 (m, 2H) 3.41-3.49 (m, 1H) 3.56-3.72 (m,3H) 4.28-4.45 (m, 2H) 4.70-4.76 (m, 1H) 5.07 (s, 2H) 6.98 (d, J=8.8 Hz,2H) 7.27-7.45 (m, 7H).

Method G Compound 134;2,2-Difluoro-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acidtriethylammonium salt

To a solution of2,2-difluoro-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acidethyl ester (0.55 g; 1.3 mmol) in THF (5 mL) and water (1 mL) was addedLithium hydroxide (0.06 g; 2.6 mmol) and stirred at 70° C. for 3 hours.After cooling to RT the reaction mixture was loaded onto a SCX-3 column[ISOLUTE (Biotage AB); 0.61 mmol/g, 15 g]. The column was washed withCH₃CN (4×15 mL) and subsequently the required compound was eluted withCH₃CN+10% Et₃N (2×15 mL). The compound containing fractions wereconcentrated in vacuo to afford2,2-Difluoro-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid asthe triethylammonium salt (0.45 g). ¹H NMR (400 MHz, Chloroform-d) δ ppm0.85-0.92 (m, 1H) 0.88 (s, 1H) 1.13 (d, J=6.32 Hz, 5H) 1.30 (t, J=7.37Hz, 10H) 1.43 (qd, J=7.22, 6.92 Hz, 1H) 1.72-1.79 (m, J=7.30, 7.30,7.07, 6.62 Hz, 1H) 2.99-3.04 (m, 1H) 3.06 (s, 1H) 3.09 (br. s., 1H)3.09-3.15 (m, 2H) 3.11 (d, J=7.52 Hz, 2H) 3.77-3.85 (m, 1H) 3.92 (t,J=6.62 Hz, 2H) 6.84 (d, J=8.73 Hz, 1H) 7.24 (d, J=8.73 Hz, 1H).

Compound 150;3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-di-fluoro-propionicacid triethylammonium salt

was obtained according to a similar manner. ¹H NMR (400 MHz, DMSO-d₆) δppm 2.18 (t, J=10.8 Hz, 1H) 2.32-2.42 (m, 1H) 2.77-2.94 (m, 4H)3.56-3.65 (m, 1H) 3.82-3.90 (m, 1H) 4.34-4.41 (m, 1H) 5.21 (s, 2H) 7.02(d, J=8.6 Hz, 2H) 7.27 (d, J=8.6 Hz, 2H) 7.44-7.50 (m, 1H) 7.56 (d,J=8.3 Hz, 2H) 10.4 (bs, 1H).

Method H Compound 135; 2-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-ethanol

To a solution of2-(4-octyloxy-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-morpholine(1.85 g; 4.4 mmol) in MeOH (10 mL) was added p-toluenesulfonic acidmonohydrate (0.84 g; 4.4 mmol) and the resulting mixture was stirred atRT for 3 hours. The reaction mixture was partitioned between 5% aqueousNaHCO₃ solution and EtOAc. The organic layer was dried (Na₂SO₄),filtered, and concentrated in vacuo to afford2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethanol (1.44 g). ¹H NMR (400MHz, CDCl₃) δ ppm 0.85-0.92 (m, 3H) 1.23-1.37 (m, 7H) 1.39-1.48 (m, 2H)1.71-1.81 (m, 2H) 2.05 (s, 1H) 2.15-2.24 (m, 1H) 2.36 (td, J=11.44, 3.31Hz, 1H) 2.53-2.62 (m, 2H) 2.79 (dd, J=11.44, 1.50 Hz, 1H) 3.32 (d,J=1.50 Hz, 1H) 3.61-3.68 (m, 2H) 3.76-3.88 (m, 1H) 3.94 (t, J=6.62 Hz,2H) 4.03 (dd, J=11.44, 1.81 Hz, 1H) 4.48 (dd, J=10.23, 2.11 Hz, 1H)6.84-6.89 (m, 2H) 7.24-7.30 (m, 2H)

Compound 141;2-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-ethanol

was obtained according to a similar manner. ¹H NMR (400 MHz, DMSO-d₆) δppm 3.06-3.28 (m, 4H) 3.48-3.66 (m, 2H) 3.81 (t, J=4.6 Hz, 2H) 3.98-4.09(m, 1H) 4.10-4.19 (m, 1H) 4.86 (d, J=10.6 Hz, 1H) 5.24 (s, 2H) 5.42(bs., 1H) 7.11 (d, J=8.6 Hz, 2H) 7.34 (d, J=8.6 Hz, 2H) 7.45-7.51 (m,1H) 7.57 (d, J=8.3 Hz, 2H) 10.9 (s, 1H)

Method I Compound 136;{3-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-propyl}-phosphonic acid

To a solution of{3-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-propyl}-phosphonic aciddiethyl ester (1.06 g; 2.26 mmol) in CH₂Cl₂ (10 mL) was addedbromotrimethylsilane (2.38 ml; 18.06 mmol) and the reaction mixture wasstirred at RT overnight. Subsequently the mixture was concentrated invacuo, redissolved in MeOH (10 mL), and stirred for 2 hours at RT. Theresulting mixture was concentrated in vacuo and treated with iPr₂O. Theprecipitate was collected by filtration and dried under vacuum to give{3-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-propyl}-phosphonic acid (0.82g; 69.8%)¹H NMR (400 MHz, DMSO-d6) δ ppm 0.75 (t, 3H) 1.06-1.25 (m, 8H)1.24-1.35 (m, 2H) 1.42-1.68 (m, 4H) 1.73-1.94 (m, 2H) 2.83-3.04 (m, 2H)3.10 (t, 2H) 3.37 (d, J=12.04 Hz, 1H) 3.43 (d, J=12.04 Hz, 1H) 3.72-3.91(m, 3H) 4.04 (d, J=12.34 Hz, 1H) 4.64 (d, J=10.83 Hz, 1H) 6.83 (d,J=8.43 Hz, 2H) 7.20 (d, J=8.43 Hz, 2H).

The following compounds were obtained according to a similar manner:

Compound 137;{2-[2-(4-Octyloxy-phenyl)-morpholin-4-yl]-ethyl}-phosphonic acid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79-0.90 (m, 3H) 1.15-1.45 (m, 9H)1.62-1.74 (m, 2H) 2.04-2.20 (m, 2H) 3.03-3.23 (m, 2H) 3.25-3.39 (m, 2H)3.57 (d, J=11.74 Hz, 1H) 3.67 (d, J=12.04 Hz, 1H) 3.84-3.99 (m, 3H)4.09-4.22 (m, 1H) 4.72 (d, J=10.53 Hz, 1H) 6.94 (d, J=8.43 Hz, 2H) 7.29(d, J=8.73 Hz, 2H).

Compound 146;(3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propyl)-phosphonicacid

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57-1.69 (m, 2H) 1.86-2.00 (m, 2H)3.05-3.27 (m, 4H) 3.47-3.65 (m, 2H) 3.90 (d, J=12.8 Hz, 1H) 4.18 (d,J=12.8 Hz 1H) 4.72 (d, J=10.9 Hz, 1H) 5.24 (s, 2H) 7.11 (d, J=8.6 Hz,2H) 7.37 (d, J=8.6 Hz, 2H) 7.45-7.52 (m, 1H) 7.58 (d, J=8.3 Hz, 2H)9.80-10.20 (bs, 1H).

Method J Compound 138; Phosphoric acidmono-{2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl}ester

A solution of phosphoric acid di-tert-butyl ester2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl ester (0.69 g; 1.31 mmol)in TFA (3 mL) and CH₂Cl₂ (3 mL) was stirred at RT for 1 hour.Subsequently, the reaction mixture was concentrated in vacuo and theresidue treated with iPr₂O. The precipitate was collected by filtrationand dried in vacuo overnight to afford phosphoric acidmono-{2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl}estertrifluoroacetic acid salt (0.42 g) 1H NMR (400 MHz, DMSO-d₆) δ ppm0.63-0.79 (m, 3H) 0.98-1.32 (m, 9H) 1.45-1.58 (m, 2H) 2.86-3.07 (m, 2H)3.13-3.28 (m, 2H) 3.29-3.47 (m, 2H) 3.68-3.83 (m, 3H) 3.89-4.06 (m, 3H)4.57 (d, J=10.53 Hz, 1H) 6.77 (d, J=8.43 Hz, 2H) 7.10 (d, J=8.43 Hz,2H).

Method K Compound 149; 2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-4-(1(2)H-tetrazol-5-ylmethyl)-morpholine hydrochloride

To 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine hydrochloride (0.30g; 0.80 mmol) was added 2 M aqueous NaOH and EtOAc. The layers wereseparated and the organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. The obtained2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine was mixed with NaI(24.0 mg; 0.16 mmol), 5-chloromethyl-1(2)H-tetrazole (0.11 g; 0.96mmol), K₂CO₃ (0.33 g; 2.40 mmol), and CH₃CN (10 mL) in a closed pyrexbottle. The resulting mixture was heated at 100° C., overnight. Aftercooling to RT the mixture was concentrated in vacuo, and the residue waspurified by column chromatography (SiO₂, EtOAc:MeOH 1:1) to afford2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-(1(2)H-tetrazol-5-ylmethyl)-morpholineThe free base was dissolved in a 4M solution of HCl in 1,4-dioxane (4mL, 16 mmol) and stirred at RT, for one hour. Subsequently the mixturewas concentrated in vacuo and the residue treated with iPr₂O. Theprecipitate was collected by filtration and dried under vacuum to afford2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-4-(1(2)H-tetrazol-5-ylmethyl)-morpholinehydrochloride (0.13 g). 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.96 (t, J=10.9Hz, 1H) 2.13-2.21 (m, 1H) 2.73-2.79 (m, 1H) 2.84-2.90 (m, 1H) 3.55-3.64(m, 3H) 3.84-3.91 (m, 1H) 4.34-4.39 (m, 1H) 5.21 (s, 2H) 7.00 (d, J=8.6Hz, 2H) 7.24 (d, J=8.6 Hz, 2H) 7.44-7.50 (m, 1H) 7.56 (d, J=8.3 Hz, 2H).

Method L Compound 228;2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-4-[2-(2H-tetrazol-5-yl)-ethyl]-morpholinehydrochloride

To a solution of3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionitrile(0.30 g; 0.77 mmol) in xylene (10 mL) was added tributyltin chloride(0.46 mL; 1.7 mmol) and NaN₃ (110 mg; 1.7 mmol). The resulting mixturewas heated at 120° C. for two days. After cooling to RT the mixture wastreated with methanol (10 mL) and concentrated in vacuo. The residue waspurified by column chromatography (EtOAc:methanol 90:10 to 50:50) toafford2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-[2-(2H-tetrazol-5-yl)-ethyl]-morpholineas the free base (0.30 g), The free base was treated with a solution ofHCl in 1,4-dioxane, after stirring at RT for 4 hours, the saltprecipitated. The salt was collected by filtration, washed with Et₂O anddried in vacuo to afford2-[4-(2,6-dichloro-benzyloxy)-phenyl]-4-[2-(2H-tetrazol-5-yl)-ethyl]-morpholinehydrochloride (0.30 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.15-3.29 (m,2H) 3.53-3.75 (m, 6H) 4.06-4.22 (m, 2H) 4.94 (d, J=11.0 Hz, 1H) 5.24 (s,2H) 7.11 (d, J=8.6 Hz, 2H) 7.36 (d, J=8.6 Hz, 2H) 7.45-7.52 (m, 1H) 7.58(d, J=8.3 Hz, 2H) 12.31 (bs, 1H).

Method M Compound 229;3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-di-methyl-propionicacid

To a suspension of3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionicacid methyl ester (1.05 g; 2.32 mmol) in THF (21 mL) and water (5.25 ml)was added LiOH (111.2 mg; 4.64 mmol). The resulting mixture was stirredfor two days at 50° C. After cooling to RT the reaction mixture wasneutralized (pH 7) with 1M aqueous HCl (4.64 mL), diluted with water (50mL)—and extracted with CH₂Cl₂ (3×50 mL). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated in vacuo. The solidresidue was triturated with ^(i)Pr₂O (10 mL) and collected by filtrationto afford3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionicacid (0.72 g) as a white powder.

Tables

Comp no. R1-A R2 R3 R4 R5 Meth. 1

H

H H A 2

H

H H A 3

H

H H A 4

H

H H A 5

H

H H A 6

H

H H A 7

H

H H A 8

H

H H A 9

H

H H A 10

H

H H A 11

H

H H A 12

H

H H A 13

H

H H A 14

H

H H A 15

H

H H A 16

H

H H A 17

H

H H A 18

H

H H A 19

H

H H A 20

H

H H A 21

H

H H A 22

H

H H A 23

H

H H A 24

H

H H A 25

H

H H A 26

H

H H A 27

H

H H A 28

H

H H A 29

H

H H A 30

H

H H A 31

H

H H A 32

H

H H A 33

H

H H A 34

H

H H B 34a

H

H H B 34b

H

H H B 35

H

H H B 36

H

H H B 37

H

H H B 38

H

H H B 39

H

H H B 40

H

H H B 41

H

H H B 41a

H

H H B 41b

H

H H B 42

H

H H B 43

H

H H B 44

H

H H B 45

H

H H B 46

H

H H B 47

H

H H B 48

H

H H B 49

H

H H B 50

H

H H B 51

H

H H B 52

H

H H B 53

H

H H B 54

H

H H B 55

H

H H B 56

H

H H B 57

H

H H B 58

H

H H B 59

H

Me H B 60

H

Me H B 61

H

Me H B 62

H

Me H B 63

H

H H B 64

H

H H B 65

H

H H B 66

3-OMe

H H B 67

3-OMe

H H B 68

3-OMe

H H B 69

2-Me

H H C 70

2-Me

H H C 71

2-Me

H H C 72

2-Me

H H C 73

2-Me

H H C 74

2-Me

H H C 75

2-Me

H H C 76

2-Me

H H C 77

2-Me

H H C 78

2-Me

H H C 79

2-Me

H H C 80

2-Me

H H C 81

2-Me

H H C 82

2-Me

H H C 83

2-Me

H H C 84

2-Me

H H C 85

2-Me

H H C 86

2-Me

H H C 87

2-Me

H H C 88

2-Me

H H C 89

2-Me

H H C 90

2-Me

H H C 91

2-Me

H H C 92

2-Me

H H C 93

2-Me

H H C 94

2-Me

H H C 95

2-Me

H H C 96

2-Me

H H C 97

2-Me

H H C 98

2-Me

H H C 99

2-Me

H H C 100

2-Me

H H C 101

2-Me

H H C 102

2-Me

H H C 103

2-Me

H H C 104

2-Me

H H C 105

2-Me

H H C 106

2-Me

H H C 107

2-Me

H H C 108

2-Me

H H C 109

2-Me

H H C 110

2-Me

H H C 111

2-Me

H H C 112

2-Me

H H C 113

2-Me

H H C 114

2-Me

H H C 115

2-Me

H H C 116

2-Me

H H C 117

2-Me

H H C 118

2-Me

H H C 119

2-Me

H H C 120

2-Me

H H C 121

2-Me

H H C 122

2-Me

H H C 123

2-Me

H H C 124

2-Me

H H C 125

2-Me

H H C 126

2-Me

H H C 127

2-Me

H H C 128

2-Me

H H C 129

2-Me

H H C 130

2-Me

H H D 131

3-CF₃

H H D 132

H

H H E 133

H

H H F 134

H

H H G 135

H

H H H 136

H

H H I 137

H

H H I 138

H

H H J 139

H

H H B 140

H

H H B 141

H

H H H 142

H

H H B 143

3-Me

H H B 144

3-Me

H H B 145

3-Me

H H B 146

H

H H I 147

H

H H B 148

H

H H B 149

H

H H K 150

H

H H G 151

H

H H F 152

H

H H B 153

H

H H B 154

H

H H B 155

H

H H B 156

H

H H B 157

H

H H B 158

H

H H B 159

H

H H B 160

H

H H B 161

H

H H B 162

H

H H B 163

H

H H B 164

H

H H B 165

H

H H B 166

H

H 5-oxo B 167

H

H 5-oxo B 168

H

H 5-oxo B 169

H

H H B 170

H

H H B 171

H

H H B 172

H

H H B 173

H

H H B 174

H

H H B 175

3-Cl

H H B 176

3-Cl

H H B 177

3-Cl

H H B 178

2-F

H H B 179

2-F

H H B 180

2-F

H H B 181

H

H H B 182

H

H H B 183

H

H H B 184

H

H H B 185

H

H H B 186

H

H 5,5-Me₂ B 187

H

H 5,5-Me₂ B 188

2-CF₃

H H B 189

2-CF₃

H H B 190

H

H 2,2-Me₂ B 191

H

H 2,2-Me₂ B 192

H

H H B 193

H

H H B 194

H

H H B 195

H

H H B 196

H

H H B 197

H

H H B 198

H

H H B 199

H

H H B 200

H

H H B 201

H

H H B 202

H

H H B 203

H

H H B 204

H

H H B 205

H

H H B 206

H

H H B 207

2-CF₃

H H B 208

2-CF₃

H H B 209

2-CF₃

H H B 210

2-CF₃

H H B 211

2-CF₃

H H B 212

2-CF₃

H H B 213

2-CF₃

H H B 214

H

H H B 215

2-Cl

H H B 216

H

H H B 217

H

H H B 218

2-CF₃

H H B 219

H

H H E 220

H

H H E 221

H

H H E 222

H

H H E 223

H

H H E 224

H

H H E 225

H

H H E 226

H

H H E 227

H

H H E 228

H

H H L 229

H

H H M 239

H

H H B

Comp no. R1-A R2 R3 R4 R5 Meth. 230

H

H H B 231

H

H H B 232

H

H H B 233

H

H H B

Comp no. R1-A R2 R3 R4 W Meth. 234

H

H S B 235

H

H S B 236

H

H S B 237

H

H S B

§5. PHARMACEUTICAL FORMULATION

A suitable example of a pharmaceutical composition according to thepresent invention is presented below.

A tablet was produced via direct compression having to the followingcomposition:

compound function amount compound 34b active 0.4-6% pharmaceuticalingredient Ac-di-Sol ® (=sodium disintegrant 3% crosscarmellose) PRUV ®(=sodium stearyl fumarate) lubricant 2% Aerosil ® (=silica) glidant 2%MCC (=micro cristalline cellulose) filler 30%  lactose monohydrate DCL15 filler rest Tablet strengths: 2, 10 and 30 mg of compound 34b/unit.Tablet weight: 500 mg.

§6. PHARMACOLOGICAL TESTS & DATA In Vitro Functional Activity (Agonism)on Human S1P5 Receptors

The CHO-human-S1P5-Aeqorin assay was bought from Euroscreen, Brussels(Euroscreen, Technical dossier, Human Lysophospholid S1P5 (Edg8)receptor, DNA clone and CHO AequoScreen™ recombinant cell-line, catalogno: ES-593-A, September 2006). Human-S1P5-Aequorin cells expressmitochondrial targeted apo-Aequorin. Cells have to be loaded withcoelanterazine, in order to reconstitute active Aequorin. After bindingof agonists to the human S1P5 receptor the intracellular calciumconcentration increases and binding of calcium to theapo-Aequorin/coelenterazine complex leads to an oxidation reaction ofcoelenterazine, which results in the production of apo-Aequorin,coelenteramide, CO₂ and light (λ_(max) 469 nm). This luminescentresponse is dependent on the agonist concentration. Luminescence ismeasured using the MicroBeta Jet (Perkin Elmer). Agonistic effects ofcompounds are expressed as pEC₅₀. Compounds were tested at a 10 pointshalf log concentration range, and 3 independent experiments wereperformed in single point's measurements.

In Vitro Functional Activity (Agonism) on Human S1P3 Receptors

The CHO-human-S1P3-Aeqorin assay (CHO/Gα16/AEQ/h-S1P₃) was establishedat Solvay Pharmaceuticals. The plasmid DNA coding for the S1P3 receptor(accession number in GenBank NM_(—)005226 was purchased from UMR cDNAresource Centre (Rolla, Mo.). The pcDNA3.1/hS1P3 construct carrying themitochondrially targeted apo-Aeqorin and Gα16 protein was transfected inCHO K1 cell-line.

Human-S1P3-Aequorin cells express mitochondrial targeted apo-Aequorin.Cells have to be loaded with coelanterazine, in order to reconstituteactive Aequorin. After binding of agonists to the human S1P3 receptorthe intracellular calcium concentration increases and binding of calciumto the apo-Aequorin/coelenterazine complex leads to an oxidationreaction of coelenterazine, which results in the production ofapo-Aequorin, coelenteramide, CO₂ and light (λ_(max) 469 nm). Thisluminescent response is dependent on the agonist concentration.Luminescence is measured using the MicroBeta Jet (Perkin Elmer).Agonistic effects of compounds are expressed as pEC₅₀. Compounds weretested at a 10 points half log concentration range, and 3 independentexperiments were performed in single point's measurements.

In Vitro Functional Activity (Agonism) on Human S1P1 Receptors

The CHO-K1-Human S1P1-c-AMP assay was performed at Euroscreenfast,Brussels (Euroscreen, Human S1P1 coupling G_(i/o)), (Edg1) receptor,catalog no: FAST-0197C, December 2009).

Recombinant CHO-K1 cells expressing human S1P1, grown to mid-log Phasein culture media without antibiotics, detached, centrifuged andre-suspended. For agonist testing cells are mixed with compound andForskolin and incubated at room temperature. Cells are lyses and cAMPconcentration are estimated, according to the manufacturerspecification, With the HTRF kit from CIS-BIO International (cat no62AM2PEB).

Agonistic effects of compounds are expressed as a percentage of theactivity of the reference compound at its EC₁₀₀ concentration, EC₅₀) iscalculated and results are reported as pEC₅₀. Compounds were tested at a10 points half log concentration range duplicated in 1 experiment.

Pharmacological data (receptor agonism) for selected compounds:

S1P5 S1P1 S1P3 Compound pEC₅₀ pEC₅₀ pEC₅₀  3 5.0 nd 4.8  16 6.0 nd 5.4 24 6.2 nd <4.5  34a 6.2 nd <4.5  34b 7.5 <5.5 <4.5  41 6.6 <5.5 5.6  535.7 nd <5.0  66 6.2 nd <5.0  76 5.6 nd <5.0  84 5.4 nd <5.0  92 5.3 nd<5.0 100 5.4 nd <5.0 117 5.4 nd <5.0 127 6.2 nd <5.0 130 7.1 <5.5 <4.5131 6.0 nd <5.0 137 7.0 nd 6.3 144 6.2 nd <5.0 150 6.2 nd <5.0 153 7.0<5.5 <5.0 164 6.5 nd 5.7 174 5.8 nd 5.3 179 6.9 <5.5 <5.0 187 6.1 nd 5.5189 6.8  5.8 5.8 196 6.0 nd nd 204 6.4 nd nd 220 6.8 nd 6.6 228 6.8 <5.5<5.0 231 6.6 nd <5.0 nd = not determined.

In Vivo Therapeutic Model; T-Maze

Age-related memory deficits occur in humans and rodents. Spontaneousalternation is the innate tendency of rodents to alternate free choicesin a T-maze over a series of successive runs. This sequential procedurerelies on working memory and is sensitive to various pharmacologicalmanipulations affecting memory processes (Aging and the physiology ofspatial memory. Barnes C. A. Neurobiol. Aging 1988:563-8; Dember W N,Fowler H. Spontaneous alternation behavior. Psychol. Bull. 1958,55(6):412-427; Gerlai R. A new continuous alternation task in T-mazedetects hippocampal dysfunction in mice. A strain comparison and lesionstudy. Behav Brain Res 1998 95(1):91-101).

For this study, male C57BL/6J mice of 2 months or 12 months old wereused in the spontaneous alternation task in the T-maze. In short, micewere subjected to 1 session containing 15 trials, consisting of 1“forced-choice” trial, followed by 14 “free-choice” trials. The animalwas considered as entering one of the arms of the maze when all fourpaws are placed within this arm. A session is terminated and the animalis removed from the maze as soon as 14 free-choice trials have beenperformed or 15 min have elapsed, whatever event occurs first. Thepercentage of alternation over the 14 free-choice trials was determinedfor each mouse and was used as an index of working memory performance.Compound 34b was administrated p.o. for 21 days prior the T-maze assayand on the day of the T-maze at t=−30 min. It was shown that compound34b at a dose of 10 mg/kg/day reversed the age-related cognitive declinein the 12-month old C57BL6J mice with 100%. Thus, treated 12 month oldmice were identical in their performance as 2 months old vehicle-treatedmice.

CONCLUSION

Compounds of the present invention have a positive effect on age-relatedcognitive decline.

1-19. (canceled)
 20. A compound of the formula (I)

or a pharmaceutically acceptable salt, solvate, or hydrate thereof,wherein R1 is selected from the group consisting of a cyano, a(2-4C)alkynyl, a (1-4C)alkyl, a (3-6C)cycloalkyl, a (4-6C)cycloalkenyl,a group selected from a (6-8C)bicycloalkyl group and a (8-10C)bicyclicgroup, wherein each group is optionally substituted with a (1-4C)alkyl,a group selected from a phenyl group, a biphenyl group, and a naphthylgroup, wherein each group is optionally substituted with at least onesubstituent independently selected from the group consisting of ahalogen, a (1-4C)alkyl optionally substituted with at least one fluoroatom, a (2-4C)alkynyl, a (1-4C)alkoxy optionally substituted with atleast one fluoro atom, an amino, a di(1-4C)alkylamino, a—SO₂(1-4C)alkyl, a —CO-(1-4C)alkyl, a —CO—O-(1-4C)alkyl, a—NH—CO-(1-4C)alkyl, and a (3-6C)cycloalkyl, a phenyl group substitutedwith a substituent selected from the group consisting of a phenoxy, abenzyl, a benzyloxy, a phenylethyl, and a monocyclic heterocycle,wherein each substituent is optionally substituted with a (1-4C)alkyl, amonocyclic heterocycle optionally substituted with a substituentselected from the group consisting of a halogen, a (1-4C)alkyl, and aphenyl optionally substituted with a (1-4C)alkyl, and a bicyclicheterocycle optionally substituted with a (1-4C)alkyl; A is selectedfrom the group consisting of —CO—O—, —O—CO—, —NH—CO—, —CO—NH, —C═C—,—CCH₃—O—, and the linking group —Y—(CH₂)_(n)—X—, wherein Y is attachedto R1 and selected from the group consisting of a bond, —O—, —S—, —SO—,—SO₂, —CH₂—O—, —CO—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO—, —C═C—, and —C≡C—;n is an integer selected from 1 to 10; and X is attached to thephenylene/pyridyl group and selected from the group consisting of abond, —O—, —S—, —SO—, —SO₂, —NH, —CO—, —C═C—, and —C≡C—; ring structureB optionally contains one nitrogen atom; R2 is selected from the groupconsisting of a H, a (1-4C)alkyl optionally substituted with at leastone fluoro atom, a (1-4C)alkoxy optionally substituted with at least oneor more fluoro atom, and a halogen; and R3 is selected from the groupconsisting of a (1-4C)alkylene-R5 wherein the alkylene group may besubstituted with a substituent selected from a (CH₂)₂ to form acyclopropyl moiety, and one or two halogen atoms, a(3-6C)cycloalkylene-R5, and a —CO—CH₂—R5; R4 is selected from the groupconsisting of H and a (1-4C)alkyl; R5 is selected from the groupconsisting of —OH, —PO₃H₂, —OPO₃H₂, —COOH, —COO(1-4C)alkyl, and atetrazol-5-yl; R6 is at least one substituent, and each R6 substituentis independently selected from the group consisting of H, a (1-4C)alkyl,and an oxo; and W is selected from the group consisting of —S—, —SO—,and —SO₂—.
 21. The compound of claim 20, wherein the ring structure B isa phenylene.
 22. The compound of claim 20, having the formula (II)


23. The compound of claim 20, wherein R3 is selected from the groupconsisting of —(CH₂)₂—OH, —CH₂COOH, —(CH₂)₂—COOH, —(CH₂)₃—COOH,—CH₂CHCH₃—COOH, —CH₂C(CH₃)₂—COOH, —CHCH₃—CH₂COOH, —CH₂CF₂COOH,—CO—CH₂COOH, 1,3-cyclobutylene-COOH, —(CH₂)₂ PO₃H₂, (CH₂)₃ PO₃H₂,—(CH₂)₂ OPO₃H₂, —(CH₂)₃ OPO₃H₂, —CH₂-tetrazol-5-yl,(CH₂)₂—tetrazol-5-yl, and —(CH₂)₃-tetrazol-5-yl; and W is —S—.
 24. Thecompound of claim 20, wherein R2 is selected from the group consistingof H, methyl, methoxy, trifluoromethyl, difluoromethyl,trifluoromethoxy, difluoromethoxy, Cl, and F; and R4 is selected fromthe group consisting of H and methyl.
 25. The compound of claim 20,wherein A is selected from the group consisting of —CO—O—, —NH—CO—,—CO—NH, —C═C—, —CCH₃—O—, and the linking group —Y—(CH₂)_(n)—X—, whereinY is attached to R1 and selected from the group consisting of a bond,—O—, —SO₂—, —CH₂O—, —CO—, —CO—O—, —NH—CO—, —C═C—, and —C≡C—; n is aninteger selected from 1 to 7; and X is attached to the phenylene/pyridylgroup and selected from the group consisting of a bond, —O—, —S—, and—NH.
 26. The compound of claim 20, wherein R1 is selected from the groupconsisting of a cyano, an ethynyl, a (1-4C)alkyl, a cyclopentyl, acyclohexyl, a cyclohexenyl, a 6,6-dimethyl-bicyclo[3.1.1]hept-2-yl, andan indanyl optionally substituted with a substituent selected from thegroup consisting of a methyl, a biphenyl, and a naphthyl, a phenyloptionally substituted with one, two or three substituents independentlyselected from the group consisting of a chloro, a fluoro, a bromo, a(1-4C)alkyl, a (2-4C)alkynyl, a (1-4C)alkoxy, a dimethylamino, atrifluoromethyl, a trifluoromethoxy, and a (3-6C)cycloalkyl, a phenylmonosubstituted with a substituent selected from the group consisting ofa phenoxy, a benzyl, a benzyloxy, a phenylethyl, a pyrazolyl, and atriazolyl, a group selected from the group consisting of a pyrazolylgroup, a thiazolyl group, an oxadiazolyl group, a thienyl group, atetrahydrofuranyl group, a pyridinyl group, and a tetrahydropyranylgroup, wherein each group is optionally substituted with a substituentselected from the group consisting of a chloro, a (1-4C)alkyl, and aphenyl substituted with a (1-4C)alkyl, and a group selected from thegroup consisting of indolyl, imidazopyridinyl, dihydrobenzofuranyl andbenzdioxanyl, each optionally substituted with (1-4C)alkyl.
 27. Thecompound of claim 26, wherein R1 is selected from the group consistingof a (1-4C)alkyl, a cyclopentyl group, a cyclohexyl group, a pyridinylgroup, and a phenyl group, wherein the latter two groups are optionallysubstituted with one or two substituents independently selected from thegroup consisting of chloro, fluoro, bromo, a (1-4C)alkyl, a(1-4C)alkoxy, and trifluoromethyl.
 28. The compound of claim 27, whereinR1 is selected from the group consisting of a (1-4C)alkyl, and adichlorophenyl.
 29. The compound of claim 22, wherein R1 is a2,6-dichlorophenyl; A is the linking group —Y—(CH₂)_(n)—X—, wherein Y isattached to R1 and is a bond, n is 1, and X is attached to the phenylenegroup and is —O—; the ring structure B is a phenylene; R2 is H; R3 is—(CH₂)₂—COOH; and R4 is H.
 30. The compound of claim 22, wherein R1 is a(1-4C)alkyl; A is the linking group —Y—(CH₂)_(n)—X—, wherein Y isattached to R1 and is a bond, n is an integer selected from 1 to 6, andX is attached to the phenylene group and is selected from the groupconsisting of —O— and a bond; the ring structure B is a phenylene; R2 isH; R3 is selected from the group consisting of —(CH₂)₂—COOH,—(CH₂)₃—COOH, —CH₂—CHCH₃—COOH, —CH₂—C(CH₃)₂—COOH, —CHCH₃—CH₂—COOH,—(CH₂)₂—PO₃H₂, —(CH₂)₃—PO₃H₂, and —(CH₂)₂—OPO₃H₂; and R4 is H.
 31. Thecompound of claim 30, wherein R1 and —(CH₂)_(n)— together form a linearoctyl group, X is —O—, and R3 is —(CH₂)₂—PO₃H₂.
 32. The compound ofclaim 20, wherein the compound is selected from the group consisting of:3-[2-(4-Benzyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid,3-{2-[4-(2-Chloro-benzyloxy)-phenyl]-thiomorpholin-4-yl}-propionic acid,3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-thiomorpholin-4-yl}-propionicacid, and 3-[2-(4-octyloxy-phenyl)-thiomorpholin-4-yl]-propionic acid,or a pharmaceutically acceptable salt, solvate or hydrate of any of theforegoing.
 33. A pharmaceutical composition comprising at least onecompound of claim 20 and at least one pharmaceutically acceptableauxiliary.
 34. A method of treating, alleviating, and/or preventing adisease and/or condition wherein any S1P receptor is involved or whereinmodulation of the endogenous S1P signaling system via any SW receptor isinvolved, the method comprising administering to a patient in needthereof a compound according to claim 20, or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof.
 35. The method of claim34, wherein the disease is a CNS disorder.
 36. The method of claim 35,wherein the CNS disorder is selected from neurodegenerative disorders.37. The method of claim 36, wherein the neurodegenerative disorder isselected from a cognitive disorder, Alzheimer's disease, (vascular)dementia, Nieman's Pick disease, cognitive deficits in schizophrenia,obsessive-compulsive behavior, major depression, autism, multiplesclerosis and pain.
 38. The method of claim 34, wherein the disease is acognitive disorder.
 39. The method of claim 38, wherein the cognitivedisorder is an age-related cognitive decline.
 40. A method for preparinga pharmaceutical composition for treating, alleviating, and/orpreventing at least one neurodegenerative disorder selected from acognitive disorder, Alzheimer's disease, dementia, Nieman's Pickdisease, cognitive deficits in schizophrenia, obsessive-compulsivebehavior, major depression, autism, multiple sclerosis and pain, themethod comprising combining at least one compound of claim 20 and atleast one pharmaceutically acceptable auxiliary.